WO2017052355A2 - Use of peptide drugs for the treatment of osteoporosis and for bone regeneration - Google Patents

Abstract

The present invention provides osteogenic peptides derived from cementum attachment protein (HACD1/CAP) and another derived from cementum protein 1 (CEMP1), and pharmaceutical compositions of said peptides for the prevention and treatment of osteopenia and osteoporosis. These peptides increased bone mineral density in an osteoporotic model, without side effects in vivo, demonstrating clinical effectiveness in the prevention and treatment of osteopenia and osteoporosis in vivo, as well as in bone repair and/or regeneration.

Description

 USE OF PEPTIDE DRUGS FOR THE TREATMENT OF

 BONE OSTEOPOROSIS AND REGENERATION

CAWIPO OF THE INVENTION

 The present invention relates to the field of medicine, new biopharmaceuticals characterized by their osteogenic properties are described, their applications and pharmaceutical compositions are described in the treatment of patients with diseases that affect bone structures such as osteopenia, osteoporosis. , and also related to its application in the area of Orthopedic Medicine and Dentistry to induce and / or increase bone formation and regeneration in a localized way including the joint use of a synthetic or natural three-dimensional scaffolding.

BACKGROUND OF THE INVENTION

 Osteoporosis is a systemic skeletal disease characterized by low bone mass and deterioration of bone tissue microarchitecture, with a consequent increase in bone fragility and fracture susceptibility {Eggertsen, 2007).

Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density of the hip or spine of 2.5 standard deviations below the normal figure determined in young people, usually expressed as a T marker of -2.5 or less. (Eggertsen, 2007, oayyeri, 2006, WHO, 2004).

Osteopenia or decrease in bone mass is defined as a bone mineral density between 1 and 2.5 standard deviations below the average of normal individuals (Eggertsen, 2007, IVIoayyeri, 2006, Sikon, 2008) is of normal occurrence during aging and It may or may not lead to osteoporosis. An individual is classified with severe osteoporosis when a fracture occurs due to insufficient bone mineral density. Osteoporosis represents a relentless epidemic of rapid growth worldwide. More than 200 million people in the world are affected by osteoporosis, of which 80% are women (NOF, 2002). In the next decade and due to the growth of the adult population and therefore the potential increase in the number of patients with osteoporosis, it will be and is necessary to establish therapeutics for the prevention and treatment of this public health problem worldwide. Likewise, osteoporosis is associated with significant morbidity, mortality and an overwhelming economic burden for those with this disease.

The National Osteoporosis Foundation in the United States of America estimates that in this country it represents a health problem for 44 million people 50 years of age and older, of which 10 million have osteoporosis and 34 million have a decrease in mining density! bone (Le., osteopenia) (NOF, 2002, Adler, 2006, Boonen, 2007). Of the ten million people with osteoporosis, 80% are women and 20% men (NOF, 2002). However, according to the 2000 US census, the number of individuals diagnosed with osteoporosis is likely to increase to 14 million men and women. Likewise, the prevalence of osteoporotic fractures increases dramatically in menopausal women (Cauley, 2006). Bone loss is more abrupt during the first decade after the establishment of menopause. Expectations in this regard are not promising since 50% of women and 20% of men are expected to present a fracture in their lifespan. Thus, the risks of women after a hip fracture equals the combined risk of breast cancer, uterine cancer and ovarian cancer and the risk of death as a result. of a hip fracture is equal to breast cancer mortality. Currently the incidence of fractures exceeds 1.5 million per year. For e! In 2025, the increase in fractures beyond 3 million is predictable, with an estimated cost of 25.3 billion dollars (Khosla, 2001). The model predicts 2.7 times the increase in fractures in the population of Hispanic origin (UN, 1998, CELADE, 2000, WBG. 2001, WHO, 2000). Spinal fractures are the most common osteoporotic fractures and are associated with activities such as weight lifting. Vertebral fractures cause back pain, curvature of the spine, reduction in lung function, and increased mortality (Delmas, 1997, Gehlbach, 2000, Klotzbuecher, 2000). Hip fractures are the second most common osteoporotic fracture and have the highest economic morbidity, mortality, impact (damage) and subsequent loss of independence (Dennison, 2006, Johnell, 2005, Orwig, 2006). Also and due to the increase in the life expectancy of the population, this type of fracture due to osteoporosis, is increasing in percentage. The third most common osteoporotic fracture is that of the distal bone of the forearm, followed by fractures of the humerus, other fractures of the femur, rib, pelvic fractures, clavicle, scapula, sternum, tibia fractures and fibular fractures (Kaukonen, 1988, Klotzbuecher, 2000).

In Latin America, the decrease in bone mineral density and bone loss is similar compared to the United States of America. The prevalence of osteopenia in women 50 years and older ranges from 45.5% to 49.6% and vertebral osteoporosis ranges from 12.1% to 17.8%. In the neck of the femur, osteopenia is present in a range of 48% to 57% and osteoporosis from 7.9% to 22% (Delezé, 2000, Santos, 2001, Lewin, 1996, Favus, 1993, Szejnfeld, 1995, Hui , 1997, ICSB, 1997). In Mexico, one in four people over 50 suffer from osteopenia or osteoporosis, approximately 24.5 million people representing 22% of the population (Riera-Espinoza 2009). From 1990 and projecting to the year 2050, the number of hip fractures in women and men from 50 to 84 years will be increased by 400%, For the age groups over 65 years, the increase will be up to 700% ( Cooper C, 1992). Of the people who suffer a hip fracture in these age groups, 17% die 4 months after the fracture. Clinical studies have determined that only 10% of the population over 70 have mining density! normal bone (Riera-Espsnoza, 2003). In Mexico, 1 in 12 women over 50 will have a hip fracture. Mortality rates in Latin America related to osteoporotic fractures range from 1.02% to 10% during your hospital stay and from 23% to 30% during the first year after the fracture. The percentage of mortality showed that this is higher in men than in women (Riera-Espinoza, 2003). The prevalence of vertebral fractures in women 50 years and older is 19.35% and in women 80 years and older, this percentage rises to 37%. In Mexican men, the prevalence of vertebral fractures is half that of Mexican women, 9.7% vs.. 19.5%, with the highest percentage in men over 80 who is 21.4% (Clark, P, 2008). This demonstrates that the impact of osteoporotic fractures in Mexican men is equal to what occurs in the rest of the world. These data support the evidence that with the increase in the incidence of fractures over the next 50 years, the magnitude of the health problem represented by the osteoporotic fracture requires extensive evaluation by health systems in the countries of Latin America and in the rest of the world (Cooper C, 1992).

Osteoporosis develops less frequently in men than in women, because bone loss begins later and progresses more slowly in men, and does not experience a period of rapid hormonal changes that is accompanied by a rapid bone loss. Differences in bone geometry and Its remodeling also contributes to a lower percentage of fractures in men (Adler, R, 2006). However, in recent years, the problem of osteoporosis in men has been recognized as a major public health problem, particularly if it is considered that the number of men older than 70 years will be double between 1993 and 2050 according to the National Osteoporosis Foundation of the United States of America. From this perspective, 1 man in 8 years of age over 50 is affected by osteoporosis and currently 2 million suffer from it and another 3 million are at risk (Burge, 2007). Each year men represent a third of all hip fractures and a third of these men will not survive more than a year and the damage caused by osteoporosis is severe and in some cases fatal. At present, there are no exact clinical or chemical tests in blood or urine that determine the abnormality that occurs during osteoporosis. The techniques currently used are mostly biochemical, radiographic markers and the measurement of bone mineral density. However, the use of these techniques is limited for reasons of cost and accuracy (Allende-Vigo, 2007, Lañe, 2006, Lata, 2007). The risk factors for menopausal women are predictive of fracture, independent of bone mineral density. Age is an independent risk factor for fractures, for every decade of life in postmenopausal women increases twice the risk of fracture. Also, the continuous and intermittent use of high doses of steroids also increases the risk of fracture. The combination of risk factors and the determination of bone mineral density improves the chances of predicting fractures.

Also, laboratory tests should be guided by history and physical examination (Reddy, 2013). The chemical panel that may be useful includes: complete blood count, thyroid gland function, vitamin D 25-OH level, eSectrophoresis of serum or urinary proteins, level of parathyroid hormone and levels of urine in the last 24 hours (Allende-Vigo, 2007, Lañe, 2006, Lata, 2007). Bone metabolism markers include markers of bone formation and resorption, which are useful in some instances to monitor e! course of therapy, but not to be used in the diagnosis of osteoporosis. Currently, a dual x-ray absorptiometry (DEXA) is considered the gold standard for the measurement of bone mineral density and osteoporosis classification (Blake, 2007, Holick, 2005, iller, 2006). The treatment of osteoporosis with non-pharmacological therapies includes preventive measures such as visual correction and improvement of hearing impairment, exercise, which helps in the maintenance of bone mineral density in menopausal women {Miller2008, Bouxsein, 2007), to the administration of Supplements such as calcium and vitamin D are considered as essential for the addition of other pharmacological therapies, since they have been shown to improve bone mineral density of the hip, but do not significantly reduce bone fractures (Parker, 2005, NA S, 2006 ). It should be noted that Sos calcium supplements frequently cause the following adverse digestive effects: constipation, flatulence and bloating, have also been linked to the increased risk of urinary stone formation. Vitamin D can cause alterations in plasma calcium concentrations, an increase in the incidence of cardiovascular disease has been described in women taking 1.5 mg daily calcium supplements, however, these results should be interpreted with caution due to limitations. methodological study and because this adverse effect has not been evidenced in any other studies with calcium. AND! Therapeutic compliance of calcium and vitamin D supplements has been poorly analyzed, a study that assessed compliance and persistence for different Drugs in women with osteoporosis detected that the lowest compliance rate was for calcium and vitamin D supplements, since only half of the patients took more than 80% of the recommended doses. Intestinal absorption of! Calcium is very low, since it is estimated that only 30% of it is absorbed! total ingested Calcium supplements come in the form of several salts: carbonate, gluconate, lactate, citrate, etc., although it has been described that there are differences in the absorption of different calcium salts, they do not seem to have clinical significance and disappear when they are They administer with food. Pharmacological therapeutics are applied in order to improve bone mineral quality and reduce the risk of fracture. These are grouped into two basic categories; anti-catabolic / anti-resortive, which include hormone replacement therapy, estrogen / anfagonist agonists, calcitonin, biophosphonates, RANKL inhibitors (Le., denosumab), and anabolic therapies such as the administration of Teriparatide (NAMS, 2008, Bonnick, 2008, Keen, 2007). Other promising therapies include the administration of strontium (Shoback, 2007). AND! Hormone replacement is an anti-catabolic therapy. Hormonal therapies that include the combination of estrogen and progesterone increase bone mineral density in post-menopausal women (IVIcCIung, 2006). In sum; The estrogen plus progesterone significantly reduce vertebral, hip, forearm and wrist fractures. AND! Hormonal replacement relieves menopause symptoms such as vaginal dryness, hot flashes and reduces the risk of colon cancer (Cauley, 2008). However, side effects include the risk of developing breast cancer, venous thromboembolism, coronary artery disease and heart attack. There is also concern about endometrial cancer in the uterus when estrogen therapy is not prescribed along with Sa progesterone therapy. However, this estrogen / hormone therapy has been approved by the FDA for Prevention of osteoporosis relief from hot flashes and vuivovagina atrophy! (Cauley, 2006). Raioxifene which is an FDA-approved drug that is an estrogen agonist receptor / antagonist and is an anti-catabolic drug and its administration increases mining density! bone in the lumbar spine, hip and neck of the femur, Reduces the risk of vertebral fractures and recently Raioxifene received additional approval from the FDA as a drug that reduces the risk of non-invasive breast cancer ( Cauley, 2006, Harris, 2005), Its side effects include the risk of venous thromboembolism and hot flashes, Calcitonin is a biological agent of the anti-catabolic class and is an FDA-approved drug for the treatment of osteoporosis, Its effects they reflect that it is useful to increase bone mineral density slightly in the spine and hip and it was determined that its administration reduces vertebral fractures, but it was not concluded if its administration provides any benefit to reduce hip fractures or non-vertebral fractures (Cummings, 1998). Because it is prescribed as a nasal spray, its side effects include occasional nasal irritation and bleeding. It also has a possible analgesic effect in patients with vertebral compression fractures (Chesnut, 2000). Biophosphonates are pyrophosphate analogues and are in the class of anti-catabolic drugs and used for the treatment of osteoporosis. Drugs containing biophosphonates and approved by the FDA are used for the prevention and treatment of osteoporosis, osteoporosis related to glucocorticoids and osteoporosis in men. These drugs have proven effective in increasing bone mineral density in the hip and spine and reduce the number of fractures of the spine, hip and non-vertebral fractures (Chesnut, 2008, Black, 1996), Major side effects With the administration of these drugs include: gastrointestinal irritation and other potential side effects include; muscle pain skeletal and osteonecrosis of the jaw. Some reports have shown that continuous treatment of biophosphonates is important for the body's response to the drug and therefore to the reduction of fractures (Liberrnan, 1995, Nevitt, 1993). Teriparatide is a recombinant biological hormone and is indicated for the treatment of post-menopausal osteoporosis and in osteoporosis in men. It is a drug made up of the first 34 amino acids of parathyroid hormone. Teriparatide increases bone mineral density in the spine and hip, decreases vertebral and non-vertebral fractures (Silverman, 2007). Its efficacy for the treatment of hip fractures has not been proven. In studies in rats, the administration of this drug is associated with the presence of osteosarcomas. Its major side effects include: hypercalcemia, leg cramps and dizziness. Due to its association with the development of osteosarcomas, the FDA has limited its administration to 24 months.

RANKL inhibitors such as Denosumab, is a monoclonal antibody produced against the kU-ligand nuclear factor activating receptor (RANKL). When Denosumab binds to RANKL, it inhibits osteoclastic formation, its function and survival and therefore the bone mineral density increases. It has been determined that Denosumab reduces vertebral, non-vertebral and hip fractures in post-menopausal women with osteoporosis (Neer, 2001). One of the potential side effects of Denosumab is osteonecrosis of the jaw, which shows a prevalence that is similar to that observed in patients using biophosphonates. The intact parathyroid hormone (PTH 1-84) and its analogue, teriparatide, represent a new class of anabolic treatment of osteoporosis. Has been described a positive effect on the improvement of bone rnicroarchitecture and a reduction in the risk of new fractures by an osteoforming mechanism. PTH 1-84 does reduce the risk of vertebral fracture but with teriparatide only a decrease in the risk of fracture has been seen but not specifically of vertebral fracture. PTH should be considered in the treatment of severe osteoporosis, both in men and women, in those patients who have several osteoporotic fractures or who have a very low bone mineral density, (T-score below -3.5) and a high risk of fracture. Other potential uses are in corticosteroid or other secondary osteoporosis. Its use is not recommended for more than 24 months with teriparatide and with PTH 1-84.

However, there is no evidence that PTH (1-84) has greater efficiency than peptide 1-34. In fact the opposite seems to be more likely. Parathyroid hormone (the 1-84 peptide) currently does not exist in the market in the USA or in Europe. Fragments of parathyroid hormone have been used as anabolic agents that stimulate bone formation. These produce substantial increases in bone density and reductions in the risk of vertebral and non-vertebral fractures. Its use is currently limited by its high cost, the need for daily injection and the concern based on studies encouraging the increase in the development of osteosarcomas. Anyway, after a decade of clinical use, there is no real evidence for this to be a concern regarding its application in humans. The beneficial, additive effects of the use of teriparatide with zolendronaio and denosumab have also been demonstrated.

Another alternative for the treatment of osteoporosis could be bone morphogenic proteins (BMPs), these constitute the most important family of growth factors to achieve bone regeneration and have a wide variety of Biological activities that include: cartilage induction, bone formation, organogenesis, proliferation and apoptosis (Gauíschi, 2007; jansen, 2005). BMPs have had application in surgeries to recover damaged bone, but the use of BfvlPs in food supplements to exert an effect on osteoporotic condition becomes complicated since the two main routes of administration, oral ingestion and topical application, do not they get the proteins to reach the bone, the BMPs tend to break before reaching the bone tissue, in addition to having seen that being soluble in water, they spread very quickly in all body fluids. It has been seen that the supply of food supplements of hydrolyzed type I collagen together with B Ps, minerals and vitamins, can contribute to bone reconstruction, but BMPs must be supplied with a carrier that protects them from! stomach environment.

Through recombinant DNA technology it has been possible to obtain adequate amounts of human recombinant morphogenic proteins (rhBMPs) for research purposes. However, its use in clinical practice is not only expensive, but also associated with adverse effects such as bone overgrowth and immunological reactions of! Guest. Recently it has been reported that short sequences of peptides from their central region could mimic the bone inductive properties of BMPs in terms of bone regeneration. Suggesting that they can be used as an alternative inducer, (Jansen, 2005; Salto, 2004; Seol, 2008; Lin XH, 2008). Morphogenic proteins (BMPs) induce endochondral bone formation by stimulating the process of differentiation of mesenchymal progenitor cells (Hogan, 1996), and have been widely evaluated in various applications including the treatment of spinal fusions, fractures, craniofacial defects and periodoniales (King; 1997; Giannobile, 1998; Geesink, 1999; Cochran, 2000; Kirker-Head, 2000; Franceschi; 2005). Only human recombinant BMP-2 and B P-7 / OP1 proteins have been approved for clinical use in humans by the FDA (Federal and Drug Adrninisíration, USA) and this is only for orthopedic and spinal fusion applications. vertebral Also, the administration of BMP-2 and BMP-7 / OP1 significantly improves the initial states of cartilage repair. However, large doses or multiple applications are required to achieve the desired osteogenic effect. On the other hand, these proteins have a half-life of 1 to 4 hours, which means that a dose of exogenous BMP apiication is equivalent to the endogenous amount present in 1000 human beings. The above represents a serious concern regarding its safety and cost (Kwon 2005). Supraphysiological concentrations as a result of an imperfect release kinetics of BMPs where 30% of the encapsulation is lost in the initial phase, have been additionally related to severe clinical complications including generalized soft tissue bruises and peri-implant bone resorption, (Gautschi, 2003 ; Bessa, 2008). Another side effect of the administration of BMP promotes excessive bone growth which results in pressure on the gastrointestinal tract and nerve roots, and they are potent inducers of arterial calcification which can predispose individual recipients to serious complications such as atheromas or thrombosis. . As we have mentioned, osteoporosis characterized by a decrease in bone mass and microarchitectural deterioration of bone tissue with the consequent bone fragility and consequent susceptibility to fractures of the hip, spine and wrist. This implies that the homeostatic balance between bone resorption and bone formation determines the mass and structural integrity of the skeleton, which is affected during the osteoporosis process. Some current therapeutic alternatives for the treatment of osteoporosis, reduce the risk of fractures osteoporotic, reducing bone resorption and preserving its architecture, but do not stimulate bone formation. Parathyroid hormone (PTH), and the B Ps do stimulate it but have the aforementioned drawbacks. Elucidating the mechanisms that regulate bone formation can lead to the development of therapies capable of reconstructing bone mass and its architecture. For now, there is a need for more therapeutic options with which you can have better results to treat this disease.

Root Cement Proteins

 Root cement is a mineralized connective tissue that covers the roots of dental organs and has unique characteristics. The physicochemical and structural characteristics of root cement are well known and have been described in detail at the morphological level. Root cement has been shown to contain polypeptides with unique location in root cement and cementblasts, these polypeptides that include root cement adhesion protein (HACD1 / CAP) and cement 1 protein (CEMP1). They play an important role in cell recruitment and differentiation during root cement formation (Aivarez. 2006).

We recently cloned and identified an mRNA from a library derived from a cell line of a human cement-ossifying fibroma, which codes for a truncated soforma of 3-hydroxyacyl-Coenzyme A-dehydratase 1 (HACD1) whose namesake is CAP. AND! CAP gene encodes for a protein of 140 amino acids of Sos which the 125 amino acids of Terminai-N are identical to HACD1, which codes for 288 amino acids. The rest of the CAP carboxy terminal constitutes the donor splicing site in exon 2 of HACD1. CAP has two transmembrane sites and the protein is truncated after the second transmembranai site. This truncation removes the sequence of HACD1 consisting of the following amino acids: ÍVHCLIGIVPT; which is the reason for active phosphatase site, which is replaced by the 15 amino acid sequence VSFPSCCFSIAVIF. CAP is then an isoform of HACD1, and alternative and homonymous spiicing of it (Valdés, 2012),

As mentioned above, the CAP codes for a product of 140 amino acids and alternative spiicing occurs exactly at the active site of the HACD, so we infer its function could be different. This alternative spücing comprises the carboxy terminal of the protein: VSFPSCCFSIAVIFM. This sequence is unique in the databases. More importantly, e! Peptide that has been synthesized has proven to possess unique properties of biological utility since it has high affinity for hydroxyapatite and also promotes the formation of hydroxyapatite crystals in vitro and its supramolecuiar organization. Cement 1 protein (CEMP1), is a 247 amino acid protein, with a

M _r of 50,000 Daitons, with post-translational modifications of glycosylation and phosphorylations; ia express cellular subpopulations of the human periodontai ligament, cement-surrounding surrounding root cement, stem cells of paravascular location in the periodontai ligament and pericytes in the alveolar bone, as well as in spinal cord cartilage and in upper and lower extremities in developing states ; CEMP1 does not show homology to any other protein, only among amino acids 30 to 110 does it show 48% similarity with collagen to chain I, 46% with type X collagen! and 40% with type X collagen. The patent application that has been submitted to the Mexican Institute of Protection

Intellectual on May 7, 2012; Application number: X / a / 2012/005314; refers to the peptide VSFPSCCFSIAVIF in tissue engineering for bone regeneration where there has been a bloody loss of bone tissue, thus achieving this technology, de novo bone formation. Mexican patent No. 324953, dated December 8, 2009, refers to obtaining pharmaceutical formulations comprising the protein of cement 1 (CEMP1), which induces the formation of root cement, bone, dentin, cartilage. and periodontal ligament and which is combined with co-glycolic polylactic acid (PLGA) which facilitates the release of the CE P1 protein.

Currently, techniques such as molecular biology and genetic engineering are used for the production of recombinant proteins, however, the complexity of the equipment, as well as preparation techniques, long production cycles, low yields and expensive processes, make it difficult to achieve large scale production. The main differences of the biopharmaceuticals produced by methods of genetically engineered expression in relation to those produced by chemical synthesis consist in the greater molecular size and the complexity of its molecular structure. By their nature, they have a poor oral bioavailability, not exceeding 1% most of the time. This is mainly due to the great enzymatic activity that exists in the digestive tract, where there is a high metabolism of peptides and proteins, and on the other hand, due to the barrier function against the absorption of these molecules in the intestinal wall! Likewise, the tissue distribution is complex, being continuously exposed to degradation by the action of proteolytic enzymes present in the blood: in general, the half-life is usually small, which is why the protein structure of some biopharmaceuticals binds to polymers (polyethylene glycol-PEG, for example) to prevent rapid renal excretion. In addition to this, there are safety problems of Sos products as a result of genetic engineering (Wozney, 2004), many biopharmaceuticals are capable of causing the generation of neutralizing antibodies, which could reduce or even cancel out their effects on their pharmacological targets. . Most biopharmaceuticals have been classified as hospital medications, in many cases, such a condition is determined by the need for close monitoring of patients during or after administration; in other cases such justification is questionable, given that some of these medications are specifically conditioned for self-administration by the patient,

To date there are no drugs that meet the requirements of a material without side effects and that are used in the treatment of osteoporosis. Osteoporosis is a pathological entity that cannot be cured in the short term, since it requires drug administration for a long period of time.

Accordingly, a different drug or biopharmaceutical is necessary that does not show any of the aforementioned side effects and that is therapeutically effective for the replacement of conventional drugs, that is of easy synthesis and finally that is economically accessible to the population for attention to this problem of public health in the world.

Considering the foregoing, the present invention relates to the use of synthetic peptides derived from root cement adhesion protein (HACD1 / CAP) and also from a peptide derived from 3rd cement protein 1 (CEÍvIPI), which promote the increase in bone mineral density, the restoration of bone microarchitecture, the restoration of physical-mechanical properties and the biological properties of bone in subjects with osteoporosis. Specifically, the present invention relates to the selection and characterization of the peptides, one of the HACD1 / CAP protein and located in the carboxyl terminal and whose sequence is AVIFM and the other peptide derived from the cement protein 1 (CEMP1) of the amino terminal amino sequence: MGTSSTDSQQAQHRRCSTSN, We refer to their uses, and formulations containing them in a pharmaceutically acceptable soluble vehicle, to promote osteogenesis; they provide the profile of biological activities to counteract the problems posed throughout the description. In the state of the art, these peptides and the properties described in the present application that make them excellent candidates for the prevention and treatment of osteopenia, osteoporosis, and the promotion of osteogenesis to maintain bone homeostasis are not described or characterized. BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Hydroxyapatite crystals induced in a cell-free system in the presence of the AVIFM peptide (20 g / mL), in a capillary counter-diffusion system. (A) flat and quadrangular homogeneous crystal microspheres of hydroxyapatite. B) The center of the microsphere shows a solid core with radiating needle-shaped hydroxyapatite crystals that radiate. (C) formation of structures using bovine serum albumin (20 pgimL), these plates do not correspond to hydroxyapatite crystals. (D) formation of structures without adding to the protest system, these plates do not correspond to hydroxyapatite crystals. (E) supramolecular organization and assembly of hydroxyapatite crystals as revealed by atomic force microscopy. (F) High resolution transmission electron microscopy (HRTE) of hydroxyapatite crystals. Figure 2: Hydroxyapathy crystals induced in a cell-free system in the presence of the MGTSSTDSQQAQHRRCSTSN peptide (20 pg / mL), in a capillary contradiffusion system. Panel (A) microspheres of flat and quadranglar homogeneous crystals of hydroxyapatite. Panel (B) the center of the microsphere shows a solid core with radiating needle-shaped hydroxyapatite cells. Panel (C) structure formation using bovine serum albumin (20 pg / mL), these plates do not correspond to hydroxyapatite crystals. Panel (D) structure formation without adding to the protein system, these plates do not correspond to hydroxyapatite crystals. (E) supramolecular organization and assembly of the hydroxyapatite crystals as revealed by atomic force microscopy. (F) High resolution transmission electron microscopy {HRTE} of hydroxyapatite crystals.

Figure 3: different spectra of X-ray Scattered Energy (EDS), with their respective Ca / P ratios and where the peaks corresponding to calcium and phosphorus are observed: A) EDS of the crystals formed in the presence of the AVIFM peptide (20 pg / mL). The Ca / P 1.53 ratio corresponds to biological hydroxyapatia. B) EDS of the crystals in the presence of bovine serum albumin (20 pg / mL). The Ca / P 1.16 ratio does not correspond to hydroxyapatite, C) EDS of the crystals formed in the sample without the addition of bovine serum albumin or any peptide. The Ca / P 1.13 ratio indicates that these crystals do not correspond to hydroxyapatite.

Figure 4: different spectra of X-ray Scattered Energy (EDS), with their respective Ca / P ratios and where the peaks corresponding to calcium and phosphorus are observed: A) EDS of the crystals formed in the presence of the MGTSSTDSQQAQHRRCSTSN peptide (20 pg / mL). The Ca / P 1.7 ratio corresponds to Hydroxyapatite of biological type. B) EDS of the crystals in the presence of bovine serum albumin (2QMg / mL). The Ca / P 1.2 ratio does not correspond to hydroxyapatite. C) EDS of the crystals formed in the sample without the addition of bovine serum albumin or aigun peptide. The Ca / P 1.1 ratio indicates that these crystals do not correspond to hydroxyapatite.

Figure 5. Microphotographs of 3 histological sections of the femoral epiphyses of Wistars rats. (A): control without treatment, normal histological characteristics of healthy bone. (B): ovarioectomízada, with consequent development of osteoporosis after ninety days and administration of saline physiological solution. (C): ovarioectomízada, with consequent development of osteoporosis, ninety days after the ovariectomy was performed, received treatment with the AVIFM peptide at a dose of 20-50 Mg / Kg weight in physiological saline solution intraperitoneally. Figure 6: Photomicrographs of 3 histological sections of rat femur epiphyses

Wistars (A): control without treatment, normal histological characteristics of healthy bone. (B): ovarioectomízada, with consequent development of osteoporosis after ninety days and administration of saline physiological solution. (C): ovarioectomízada, with consequent development of osteoporosis, ninety days after the ovariectomy, received treatment with the MGTSSTDSQQAGHRRCSTSN peptide at a dose of 20-50 pg / kg weight in physiological saline solution intraperitoneally.

Figure 7: Photomicrographs of 8 histological sections of the body of the 5 ^, lumbar vertebra in the transverse and sagittal planes. (A) corresponds to the image of the lumbar vertebra ^{May 4} in the sagittal (a ') normal Wistar rats transverse planes (a) and. (B) corresponds to the 5 lumbar vertebrae ^ed in the transverse and sagittal planes (b) (b ') Wistar rat osteoporotic treated with physiological saline. It panel (C), corresponding to the 5 ^th lumbar vertebrae in transverse planes! (c) and sagittal (c ') of Wistar rat treated with the AVIFM peptide at a dose of 20-50 pg / kg weight and for 90 days of daily administration intraperitoneally.

Figure 8: Histological sections 8 photomicrographs body 5 ^th lumbar vertebrae in the transverse and sagittal planes. (A) corresponds to the image of 5 ^ed lumbar vertebra in transverse planes! (a) and sagittal (a ') of normal Wistar rat. (B) corresponds to the 5 lumbar vertebrae ^ed in cross pianos (b) and sagittal (b ') Wistar rat osteoporotic treated with physiological saline. Panel (C) corresponds to Sa 5 ^ta lumbar vertebra in the transverse (c) and sagittal (c ') planes of Wistar rat treated with the MGTSSTDSQQAQHRRCSTSN peptide at a dose of 20-50 pg / kg weight and for 90 days of daily administration intraperitoneally. Figure 9: Photomicrographs of histological sections of tissues of normal Wistar rats and ovarioecomyzed Wistar rats that developed osteoporosis. (A) tissues in health status of Wistar rat without osteoporosis: (B) tissue of Wistar raffles that developed osteoporosis and to which the AVIFM peptide was administered at a dose of 20-50 pg / kg weight in physiological saline solution via intraperitoneal and for 90 days. H-liver, R-kidney, Co = heart, P = puimon, Ce = brain, Ba = Spleen, = Muscle. There is no histological characteristic that indicates that administration of the peptides in saline physiological solution causes any microscopic alteration of these tissues. Figure 10: Photomicrographs of histological sections of tissues of normal Wistar rats and ovarioectomized Wistar rats that developed osteoporosis. (A) tissues In the health era of Wistar raía without osteoporosis: (B) tissue of Wistar rats that developed osteoporosis and to which the MGTSSTDSQQAQHRRCSTSN peptide was administered at a dose of 20-50 pg / kg weight in physiological saline solution intraperitoneally and during 90 days. f- liver, R = kidney. Co ^ heart, P ~ pulrnán, Ce = brain, Ba-Spleen, M ~ Muscle. There is no histological characteristic that indicates that the administration of the peptides in saline physiological solution causes some microscopic alteration of these tissues.

Figure 1 1: CT images microíomografía (μΟΤ) of the vertebral body 5 ^th lumbar vertebrae of Wistar rats (A) not subjected to ovariecíomía group and received no treatment; (B): from group ai that underwent ovariectomy and did not receive treatment; (C): from the group that underwent ovariectomy and 5 months later the treatment with the peptide derived from the adhesion protein of! root cement (HACD1 / CAP): AVIFM, at a concentration of 20-50 pg / Kg weight dissolved in saline physiological solution, and injected intraperitoneally, daily and for 90 days: computerized microtomography images (μΟΤ) of the vertebra body! 5th ^ed lumbar vertebra of Wistar rats group (D) not subjected to ovariectomy and received no treatment; (E): of the group that underwent ovariectomy and did not receive treatment; (F): from the group ai that underwent ovariectomy and 5 months later the treatment with the peptide derived from the cement protein 1 (CEMPI) was started: MGTSSTDSQQAQHRRCSTSN, at a concentration of 20-50 μgίKg weight dissolved in physiological solution saline, and injected intraperitoneally, daily and for 90 days. Boxes with magnification are presented for each image. Figure 12: Compressive strength of the body of the 5 ^th lumbar vertebrae of normal Wistar rats (control), osteoporosis (OVX) and osteoporosis receiving treatment than with any of the peptides of the invention. (A): AVIFM. (B): MGTSSTDSQQAQHRRCSTSN; at a dose of 20-50 ug / kg weight and for 90 days of daily administration intraperitoneally !, respectively. The measurements were made at the end of the treatment.

Figure 13: Specific activity of serum alkaline phosphates extracted from normal (control) Wistar rats, with osteoporosis (OVX) and with osteoporosis who received treatment with any of the peptides: (A): AVIFM, (B); GTSSTDSQQAQHRRCSTSN; at a dose of 20-50 pg / kg weight and for 90 days of daily administration intraperitoneally! The specific activity of alkaline phosphatase was determined at the beginning and at the end! of treatment

Figure 14: Levels of circulating osteocalcin in serum extracted from Wistar rats, determined by ELISA, at the beginning and at the end of the experimental period that was 90 days after a period of 5 months after the ovariectomy was performed. Serum of 8 healthy Wistar (control) rats, 8 ovary-ectomized Wistar rats that received intraperitoneal saline physiological solution for 90 days (OVX) and (A) treatment: 8 osteoporotic ovary-ectomized Wistar rats treated with the AVIFM peptide, or ( B) treated with the MGTSSTDSQQAQHRRCSTSN peptide; both at a concentration of 20-50 pg / kg weight dissociation in physiological saline solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy.

Figure 15: Concentration of the activating receptor ligand for circulating nuclear factor B (RANKL) in serum extracted from Wistar rats at the beginning and at the end of the experimental period that was 90 days after a period of 5 months of performing a ovariectomy. RANKL levels were determined by ELISA assay at from the serum of 8 healthy Wistar (control) rats, 8 ovary-ectomized Wistar rats that received intraperitoneal saline physiological solution for 90 days (OVX) and 8 osteoporotic ovarian-ectomized Wistar rats treated with any of the peptides of this invention (A): AVIFM, or (B): IVSGTSSTDSGQAQHRRCSTSN; at a concentration of 20-50 ug / kg weight dissolved in physiological saline solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy.

Figure 18: Level of circulating osteoprotegerin (OPG) in serum extracted from Wistar rats at the beginning and at the end of the experimental period that was 90 days after a period of 5 months after the ovariectomy was performed. Osteoprotegerin levels were determined by ELISA assay from the serum of 8 healthy Wistar (control) rats, 8 ovary-ectomized Wistar rats that received intraperitoneal saline physiological solution for 90 days (OVX) and 8 rats as treatment. Osteoporotic ovarioectomized Wistar treated with any of the peptides, (A): AVIFM, or (B): MGTSSTDSQQAQHRRCSTSN; at a concentration of 20-50 pg / kg weight dissolved in saline physiological solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy. Figure 17: Biodistribution of the peptides object of this invention of the peptide

AVIFM with brand of pertecnectate (Tc04-), levels detected in the different tissues and blood of Raías Wistar.

Figure 18: Biodistribution of the peptides object of this peptide MGTSSTDSQQAQHRRCSTSN pertecnectate (Tc04-)., Levels detected in the different tissues and blood of Wistar Rats. Figure 19: Cytotoxicicfad and in vitro proliferation using the peptides object of this invention (A): AVIFM, or (B): MGTSSTDSQQAQHRRCSTSN at increasing concentrations; 1, 3 and 5 g / ml.

Figure 20: icrophoto of the histological section of a thickness of 5 μΓΠ and showing e! Critical size defect in Wistar rat caivaria. (A) no treatment, after 16 weeks, (B) critical size defect was covered with the three-dimensional jelly-based scaffold, after 18 weeks, (C) treatment with the three-dimensional scaffold formulation + 20-50 pg of the AVIF peptide after 16 weeks.

Figure 21: Photomicrograph of the histological section of a thickness of 5 pm and showing the critical size defect in Wistar rat caivaria, (A) no treatment, after 18 weeks, (B) critical size defect was covered with the scaffold three-dimensional gelatin-based, after 18 weeks, (C) treatment with the formulation of the scaffold irresizeai + 20-50 pg of the peptide MGTSSTDSQQAQHRRCSTSN after 16 weeks.

DETAILED DESCRIPTION OF THE INVENTION Deposition of mining tissue! Bone and bone regeneration is required for the cure of certain diseases, and / or sequelae of osteopenia, osteoporosis, osteoarthritis. To correct the alterations that these pathological entities cause on bone structures, pharmacological treatment is required to prevent and regenerate bone structures. The present invention provides artificially synthesized peptides that promote the synthesis of hydroxyapatite and that generates osseo-inductive signals, thus constituting an alternative to one of the fundamental elements to contribute to bone mineral tissue deposition and regeneration. bone bone and in general for the development of technologies in the field of bone mineral tissue engineering.

The invention provides peptides that pursue a defined biological activity; These peptides are fragments of the protein sequences derived from root cement: root cement adhesion protein (HACD1 / CAP) and cement protein 1 (CE P1), these peptides consist of sequences of 5, and 20 amino acids defined as SEQ ID NO: 1 and SEQ! D NO: 2 in the sequence listing, respectively, can be used with an inert diluent such as physiological saline solution pH 7.4 in a pharmaceutical formulation to favor the osteogenesis process and inhibit the resorption process bone in vivo,

The present invention provides pharmaceutical compositions containing any of these peptides or both, which can be administered prophylactically and / or as an inducer, and / or as a promoter with therapeutic utility whose purpose is to increase bone mineral density, recover the microarchitecture bone, recover the physical-mechanical properties and biological properties of bone tissue that are affected during osteopenia and osteoporosis and also promote bone regeneration in vivo. This invention is advantageous since these peptides prevent the loss of bone mineral density and its collateral effect such as vertebral, hip, femoral head fractures and others associated with osteoporosis, both in men and women. The therapeutic utility of these peptides are related to the process of bone remineralization so that it occurs faster and without adverse side reactions; which can finally improve the clinical effectiveness index, as well as positively impacting the cost of treatment. These peptides are then very useful for prophylaxis and for the treatment of osteopenia and osteoporosis and bone regeneration. This invention describes the specific formula, as well as the sequence of the peptides, methods of preparation and the uses that are presented within the scope of this invention,

The peptides related to the present invention have been synthesized by conventional biochemical methods. The synthesis of these peptides preserves the biological activity properties of the native proteins and of the human recombinant proteins; root cement adhesion protein (HACD1 / CAP) and cement 1 protein (CEMP1), so that the function of the peptides is similar to that of root cement adhesion proteins (HACD1 / CAP), cement protein 1 (CEMP1), to the recombinant proteins HACD1 / CAP and CE P1. The present invention provides an alternative to increase bone mineral density, promote bone mineral tissue deposition and bone formation and / or regeneration.

The capacity of! peptide of the invention to inhibit the bone resorption process, promote osteogenesis, including bone mineral tissue deposition, regeneration and / or repair of normal bone conditions that have been lost due to osteoporosis. The tests include in vitro results and experimental studies in an osteoporotic model in Wistar rats in vivo, as well as bone regeneration in critically sized defects in calvarias in preclinical studies in Wistar rat calvarias.

As already mentioned, the structure of the biologically active peptides derived from the cement adhesion protein (HACD1 / CAP) are: AVIFiVS (SEQ ID NO: 1), or the cement protein 1 (CEMP1); GTSSTDSQQAQHRRCSTSN (SEQ ID NG: 2). These peptides were used included in an injectable pharmaceutical formulation whose vehicle is physiological saline solution, whereby said combination is a preferred embodiment of the invention. The pharmaceutical formulation disclosed in the present invention can increase bone mineral density, promote bone mineral tissue deposition and bone tissue regeneration, which has been or damaged as a result of a systemic disease such as osteoporosis and recover the related qualities. to bone size, bone morphology and microarchitecture and bone material and biomechanical properties. Likewise, it is demonstrated that these peptides are capable of regulating the supramolecular organization of nanospheres that constitute the hydroxyapatite crystals and therefore as initiators and regulators of the biomineralization process. Additionally, it is demonstrated that these peptides regulate the serum levels of the biochemical markers that participate in the biological process of resorption and / or deposition of the components of the bone extracellular matrix and bone mineral deposition.

Synthetic peptides with a purity of 95% representing the carboxyl terminal of the human cement adhesion protein (HACD1 / CAP), with the AVIF sequence, or the sequence representing the amino terminal of the cement protein 1 (EC P1), MGTSSTDSQQAQHRRCSTSN, are synthesized by the conventional FfvIOC / tBu method in solid phase synthesis.

In order to obtain the benefits of the use of peptides derived from the cement adhesion protein (HACD1 / CAP): AVIFM, and of the cement protein 1 (CEMPI); MGTSSTDSQQAQHRRCSTSN; artificially synthesized, the formulation was prepared Pharmaceutical mentioned for the purpose of proper administration. This pharmaceutical formulation is within the modalities of the invention, but it is not limited to the scope of use that the peptide may have: this formulation consists of dissolving the peptide at a concentration of 20 ug / kg weight in physiological saline solution as described in various formulations of therapeutic products approved by the US Food and Drug Administration (FDA), whose purpose in this formulation is to facilitate the release of the peptides of the invention for their therapeutic utility or as a regulator and modifier of the therapeutic response in induction for The deposition of bone mineral tissue and bone tssular regeneration in systemic skeletal disorders characterized by low bone mass and involvement of bone tissue microarchitecture as occurs in osteopenia and osteoporosis.

As experimentally demonstrated and as described below, these peptides significantly stimulate natural bone matrix deposition and guide the biomineraization process. The peptides can facilitate the self-assembly of nanospheres and bidroxyapatite nucleation and allow their growth in a structure similar to that which occurs in natural bone !, whereby the peptides object of this invention can function in a similar way to a protein native or recombinant and regulate the expression of molecules associated with the bone resorption / regeneration process such as alkaline phosphatase (ALP), osteocalcin (OCN), osieoprotegerin (OPG) and the activating receptor ligand for nuclear factor B ( RANKL) giving everything as a whole, the increase in bone mineral density that is reflected in the mechanical resistance to compression with values similar to healthy bone. In the present invention, artificially synthesized and conjugated peptides with saline physiological solution at a concentration of 20-50 pg / kg weight were used. Be The experimental model of induction of hydroxyapatite crystal formation was carried out in vitro and the experimental model of osteoporosis was carried out in Wistar rats and the treatment of this with any of the described peptides object of this invention. Based on the experiments described below, we demonstrate that the peptides, object of this invention can be used individually for the treatment of osteoporosis as described in example 1.

The results obtained are presented in Figures 1 and 2, where we observe the induction of hydroxyapatite crystals in a cell-free in vitro system, by means of any of the peptides object of this invention and corresponding to the following sequences of the Root cement adhesion protein (HACD1 / CAP): AVIFM, or Cement Protein 1 (CE P1): IvIGTSSTDSQQAQHRRCSTSN; used at a concentration of 2Qpg / rnL in a counter-diffusion system in metasilicate geys, where the peptides were incubated, separately, for 7 days at a temperature of 37X, at a concentration of 20 μgίL · in semi-solid gelsytasis of metasiiicate sodium.

As seen in Figures 1 (A) and 2 (A), any of the peptides promotes the formation of microspheres composed of homogeneous crystals whose termination is in the form of an arrow, presenting bevelled terminations (insert) and corresponding to hydroxyapatite crystals .

In figures 1 (B) and 2 (B), the interior of a microsphere is observed where the nucleus of the latter is observed and from which crystals radiate that initially have the shape of a needle and along its extension form crystals flattened and corresponding to hydroxyapatite crystals. In figures 1 (C) and 2 {C) the formation of crystals in a flat and plaque-like form is observed with the use of a control protein that in this case bovine serum albumin was used at a concentration of 20 pg / mL, These plate-shaped crystals do not correspond to hydroxyapaite.

Figures 1 (D) and 2 (D) show the formation of plaque-shaped crystals, however in this control no protein was used and they do not correspond to hydroxyapatite crystals. In figures 1 (E) and 2 (E), the hierarchical organization and self-assembly of nanospheres that are arranged in chains is observed due to the alignment and fusion of the original nanospheres. The appearance of the nanospheres is homogeneous although some nanocomponents represent nano-chains. In Figures 1 (F) and 2 (F) e! Analysis of the hydroxyapatite crystals by means of high-resolution transmission electron microscopy (HRTEM), showing the near interplanar distance planes 1 15 and 225 in the direction of the crystalline phase of the hydroxyapatite.

Figures 3 and 4 show the different X-ray Scattered Energy (EDS) spectra, to determine the composition of the crystals formed by the action of the aforementioned peptides with their respective Ca / P ratios and where the peaks corresponding to calcium are observed and to the match. Also, Sos spectra of controls with bovine serum albumin (20 pg / mL) are shown. The Ca / P ratio 1.16 to 1.2 presented in panel B of Figures 3 and 4 does not correspond to hydroxyapatite. The Ca / P ratios according to the spectra obtained from the crystals induced by each of the motive peptides of this invention were between the Ca / P ratio 1.5 to 1.7, which are in the hydroxyapatite type range Biological (Joint Committee on Powder Diffraction Standars No. 9-432 file for calcium hydroxyapatite) (JCPDS, 1998) this is observed in the pane! A of Figures 3 and 4 for each peptide (HACD1 / CAP): A IFM or of Sa cement protein 1 (CEMP1): GTSSTDSQQAQHRRCSTSN. In the C panel of Figures 3 and 4 the crystals that were formed without the presence of any protein and whose Ca / P ratio is equal to 1.1 and does not correspond to hydroxyapatite are observed. Figures 5 and 6 show the histological sections of 5 μ? Η thick and stained with Masson's Trichrome stain in which the microarchitecture of the Wistar rat femur epiphysis is analyzed in detail. The letter (A) of both figures 5 and 8 corresponds to! group without any treatment and is a healthy control group. In the histological section stained with Masson's Trichrome stain, the normal microarchitecture of the epiphysis of the femur with spongy bone and the medullary spaces filled with bone marrow and bone is observed occupying the intermedullary spaces and the epiphyseal plate and articular cartilage are also observed . Letter (B) of both figures 5 and 6 shows the microarchitecture of the epiphysis of the Wistar rat femur and corresponding to the group that underwent ovariectomy, who developed osteoporosis and who received as a treatment the injection of the vehicle (physiological saline solution ) after 5 months of performing the ovariectomy. The treatment with the vehicle lasted 90 days. The analysis of the tissues at the end of the experimental period with saline physiological solution reveals in the photomicrograph the histological characteristics of the Wistar rat femur epiphysis. The microarchitecture is observed where the medullary spaces in the epiphysis do not contain bone marrow, so they are empty, so the bone looks porous and gives the appearance of a sponge. These spaces are observed of varying dimensions. The articular cartilage and epiphyseal plaque are observed. Letter (C) of both figures 5 and 8, shows Sa microarchitecture of the epiphysis of the Wistar rat femur corresponding to the group that underwent ovariectomy and developed osteoporosis and that received as a treatment the pharmaceutical formulation consistent with any of the peptides Root cement adhesion protein derivatives (HACD1 / CAP): AVIFIV1 or protein cement 1 (CEMP1): MGTSSTDSQQAQHRRCSTSN; at a concentration of 20-50 pg / kg weight, dissolved in physiological saline solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy. The micrograph shows the microarchitecture of the epiphysis of the femur of Raía Wisíar. This histological section stained with asson Trichrome staining and where the normal microarchitecture of the epiphysis of the femur with spongy bone is observed and where the medullary spaces are observed filled with bone marrow and bone occupying the intermedullary spaces and the epiphyseal plate is also observed and articular cartilage. This photomicrograph with the histological characteristics demonstrates that the Wistar rats undergoing ovariectomy, which developed osteoporosis and were treated with the peptide object of this invention, shows the characteristics of healthy normal bone.

Figures 7 and 8 show microfotog raffias of histological sections of 5 pm in thickness of the body of the 5 ^! Lumbar vertebra in the transverse and sagittal planes, stained with Masson's Trichrome Staining. Panel (A) of Figures 7 and 8 corresponds to the body of the 5 ^th lumbar vertebrae in the transverse planes (a) and sagittal ^(a!) Rat Normal Wistar where you can observe the cortical bone, trabecular bone and the spaces occupied with bone marrow. The panel (B) of Figures 7 and 8, corresponds to the body of the 8 ^to lumbar vertebra in the transverse (b) and sagittal (b ¹ ) planes of osteoporotic Wistar rat treated with physiological saline. the bone trabeculate of a thinner thickness than the healthy Wistar rats and the medullary spaces between the bone trabeculate occupied by fatty tissue, these spaces being of greater area if compared with the healthy control. Panel (C) of Figures 7 and 8 corresponds to the body of the 5 ^Í8 lumbar vertebra in the transverse (c) and sagittal (c ^! ) Pianos of Wistar rat treated, respectively, with the AVIFM peptide or the SvlGTSSTDSQGAQHRRCSTSN peptide at a dose of 20-50 pg / kg weight and for 90 days of daily administration intraperitoneally, the bone cortex similar to that presented by healthy Wistar rats is observed and a dense and well organized bone trabeculate is observed with the spaces occupied by bone marrow, Figures 9 and 10 show photomicrographs of! histological section of a thickness of 5 pm and showing the histological characteristics of various tissues of Wistar rats that do not have osteoporosis and Wistar rats subjected to ovariectomy, which developed osteoporosis and were treated with any of the synthetic peptides, object of this invention derived from Root cement adhesion protein (HACD1 / CAP): AVIPy or protein! Cement 1 (CE PI): MGTSSTDSGGAQHRRCSTSN; at a concentration of 20-50 pg / kg weight dissolved in physiological saline solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy. The control tissues in Panel A correspond to: normal tissues: H = liver, R = kidney, Co ^ heart, P-lung, Ce ^ brain, -muscle, Ba ~ Spleen. Pane! B) tissues of Wistar rats with osteoporosis and treated with the pharmaceutical formulation object of this invention; H = liver, R ~ kidney, Co ^ heart, P = lung, Ce = brain, Ba = Spleen M ^ muscle. There are no microscopic differences in the tissues, nor alterations in the microarchitecture of these, so the tissues treated experimentally with the peptides object of this invention do not produce cellular, tissue, or morphological alterations, observing normal and similar characteristics to those of A healthy subject. This implies that synthetic peptides are harmless as drugs for the treatment of osteoporosis, not producing adverse or secondary reactions at the cellular or tissue level. Figure 1 1 presents images obtained through computerized microtomography (pCT) and three-dimensional reconstruction of the vertebra body! 5th ^ed vertebra lumbar of Wistar raias that were not subjected to ovariectomy and is therefore representative of the healthy control group, of group a! that he underwent ovariectomy and that he was not treated with any of the peptides object of this invention and of the group that underwent ovariectomy and 5 months later the treatment with any of the synthetic peptides, object of this invention was initiated , root cement adhesion protein derivatives (HACD1 / CAP): AVIFM or Cement Protein 1 (CEMP1): MGTSSTDSQQAGHRRCSTSN; at a concentration of 20-50 Mg / Kg weight dissolved in saline physiological solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy.

Group treated with pépfido AVIFM and controls: Panel A) the image is observed superior-inferior of 5 ^ed lumbar vertebra healthy control group, especially the body of this, with all its anatomic components including the transverse processes, the spinous process, the vertebral hole, where we observe the bone cortex as a compact line, as well as the spongy bone occupying the entire space of this anatomical entity, without presenting spaces. This is corroborated in the insert where trabecular structures and spinal spaces are observed in detail. Panel B) image obtained through computerized microtomography of the 5 ^Sa lumbar vertebra of Wistar rat undergoing ovariectomy, which developed osteoporosis and which received as a treatment the vehicle of this pharmaceutical formulation consisting of physiological saline solution injected intraperitoneally for 90 days. The vertebral anatomical characteristics are observed in a supero-inferior position and described in the pane! (TO). The three-dimensional reconstruction indicates that the vertebral body has spinal spaces of greater size and decrease in bone trabeculae as well as their thickness. The inserted image shows in detail that the spongy bone, whose spaces appear larger and areas where the absence of bone is evident spongy. Panel C) image obtained via computed microtomography ed 5 ^ed lumbar vertebra Wistar rats underwent ovariectomy, who developed osteoporosis and received as treatment the pharmaceutical formulation consisting of either peptide object of this invention derived from to adhesion protein of root cement (HACD1 / CAP); AVIF at a concentration of 20-50 pg / kg weight dissolved in saline physiological solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy. In the three - dimensional reconstruction, the image is observed in the superior-inferior lumbar vertebra 5 ^ed with all its anatomic components. The three-dimensional image shows the electrodense cortex of the body of the vertebra as well as the spongy bone with small spaces and where the spongy bone is present in almost the entire vertebral body.

Group treated with the peptide GTSSTDSQQAQHRRCSTSN and controls: Panel D) shows the image superior-inferior of 5 ^ed lumbar vertebra healthy control group, particularly the body thereof, with all its anatomic components including ies transverse processes, ia spinous process, the vertebral hole, where we observe the bone cortex as a compact line, as well as the spongy bone occupying the entire space of this anatomical entity, without presenting spaces, This is corroborated in the insert that where trabecular structures are observed in detail and the core spaces. Panel E) image obtained through computerized microtomography of ia 5 ^¾ lumbar vertebra of Wistar rat undergoing ovariectomy, which developed osteoporosis and received as a treatment the vehicle of this pharmaceutical formulation consisting of physiological saline solution injected intraperitoneally for 90 days. The vertebral anatomical characteristics are observed in a supero-inferior position and described in the panel (A). The three-dimensional reconstruction It indicates that the vertebra body! It presents spinal spaces of greater size and decrease in bone trabeculae as well as their thickness. The inserted image shows in detail that the spongy bone, whose spaces appear larger and areas where the absence of spongy bone is evident. Panel F) image obtained using computed microtomography ed 5 ^th lumbar vertebra Wistar rats underwent ovariectomy, who developed osteoporosis and received as treatment the pharmaceutical formulation consisting of either dei peptide object of this invention derived from the protein cement 1 (CEMP1) at a concentration of 20-50 Mg / Kg weight dissolved in physiological saline solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy. In three-dimensional reconstruction, the supero-inferior image of the 5 ^! Lumbar vertebra with all its anatomical components is observed. The three-dimensional image shows the electrodense cortex of the vertebra body as well as the spongy bone with small spaces and where the spongy bone is present in almost the entire body of the vertebral body.

Figure 12 corresponds to a graph where the resistance shown Sa compression dei vertebral body 5 ^to lumbar vertebra obtained Wistar rats at the end of the experimental period was 90 days after a period of 5 months performed ed ovariectomy. Resistance tests were performed using the Instron Universal Testing Machine (mod. 5567) Ei body 5 ^th lumbar vertebra with a compressed speed 1mm / min to achieve fracture of the sample. The force exerted is expressed in N / mm ² . The vertebral bodies of ia 5 were analyzed ^, lumbar vertebra of 8 healthy Wistar rats, 8 ovarian-ectomized Wistar rats and received as treatment for intraperitoneal saline physiological solution injection for 90 days and 8 osteoporotic ovarian-ectomized Wistar rats treated with any of the peptides Object of this invention derived from Sa Root Cement Adhesion Protein (HACD1 / CAP): AVIF or Cement Protein 1 (CEfV! PI): MGTSSTDSGQAGHRRCSTSN at a concentration of 20-50 pg / Kg weight dissolved in physiological saline solution , and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomfa. Corno shown in graph A of Figure 12, levels the resistance of the vertebral bodies of the 5 ^th lumbar vertebra of osteoporotic rats (OVX) show a decrease of compressive strength of 53%, osteoporotic rats and treated with the AVIFM peptide object of this invention have similar values with healthy control rats of compressive strength, exhibiting a 2% difference from the control. As can be seen in graph B of Figure 12, the levels of resistance of the vertebral bodies of the 5th lumbar vertebra of the osteoporotic rats (OVA) show a 58% decrease in compressive strength. Osteoporotic rats and treated with e! Peptide GTSSTDSQQAQHRRCSTSN object of this invention have similar values with healthy control rats of resistance to Sa compression, exhibiting a difference of 19% with respect to the control. These results indicate that the treatment of osteoporosis with any of the peptides, object of this invention promotes compressive strength and fracture resistance similar to! healthy control bone, indicating that any of these peptides promote increased bone mineral density.

Figure 13 corresponds to the graphs of the specific activity of serum alkaline phosphatase extracted from Wistar rats at the beginning and at the end of the experimental period that was 90 days after a period of 5 months of performing the ovariectomy. The specific activity of alkaline phosphatase was analyzed from the serum of 8 healthy Wistar rats, 8 ovarian-ectomized Wistar rats that received intraperitoneal injection of saline physiological solution for 90 days and 8 Wistar rats as treatment Osteoporotic ovarioectom treated with any of the peptides object of this invention derived from root cement adhesion protein (HACD1 / CAP): AVIFM (Figure 13A) or cement protein 1 (CEMP1): V1GTSSTDSGGAQHRRCSTSN (Figure 13B); at a concentration of 20-50 pg / Kg weight dissolved in saline physiological solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy. As can be seen in the graph at the beginning of treatment, osteoporotic rats show a 53% increase in serum alkaline phosphatase specific activity with respect to the values of this same enzyme in normal healthy rats. At 90 days, at the end of treatment, osteoporotic Wistar rats treated with any of the peptides object of this invention show a reduction of 1% difference with respect to healthy controls Wistar rats and a decrease of! 48% with respect to the specific activity of alkaline phosphatase that remains high in osteoporotic rats that received as a treatment the vehicle used in this pharmaceutical formulation and that is physiological saline. These results indicate that the peptides, object of this invention are capable of regulating the specific activity of the alkaline phosphatase and therefore the peptide participates in the process of bone remineraiization in the treatment of osteoporosis. Figure 14 corresponds to a graph showing the circulating osfeocalcin in serum extracted from Wistar rats at the beginning and at the end of the experimental period that was 90 days after a period of 5 months of performing ovariectomy. Osteocalcin levels were determined by ELISA assay (enzyme-linked immunosorbent assay), from the serum of 8 healthy Wistar rats, 8 Wistar ovarioectom rats raised and treated as intraperitoneal saline physiological solution for 90 8 days and ovarioectomized Wistar rats osieophoresics treated with any of the peptides object of this invention derived from the root cement adhesion protein (HACD1 / CAP): AVÍFM (Figure 14A) or the cement protein 1 (CEMP1): MGTSSTDSQQAQHRRCSTSN (Figure 14B); at a concentration of 20-50 Mg / Kg weight dissolved in physiological saline solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy.

As can be seen in the graph, the levels of serum osteocaine increases by 174% with respect to the levels of osteocaine determined in the serum of healthy control raffles. However, at 90 days after the treatment of osteoporotic rats with the vehicle used in this pharmaceutical formulation and which is a physiological saline solution, serum osteocaine levels increase up to 205%, while osteoporotic rats treated with any of the peptides object of this invention show a reduction of 61% when compared with osteocaine values in osteoporotic rats without treatment with any of the peptides. This indicates that the administration of any of the peptides object of this invention promotes the decrease in serum osteocaine levels when compared to osteoporotic rats without treatment, indicating that the peptides promote the process of bone remineralization.

Figure 15 corresponds to a graph showing the activator receptor ligand for e! circulating nuclear factor B (RANKL) in serum extracted from Wistar rats at the beginning and at the end of the experimental period that was 90 days after a period of 5 months of performing the ovariectomy. RANKL levels were determined by ELISA assay (enzyme-linked immunosorbent assay), from the serum of 8 healthy Wistar rats, 8 ovarioectomized Wistar rats and received as Intraperitoneal injection of saline physiological solution for 90 days and 8 osteoporotic ovary-ectomized Wistar raises treated with any of the peptides object of this invention derived from the root cement adhesion protein (HACD1 / CAP): AVIFSvl (Figure 15A) or Cement 1 protein (CE P1): MGTSSTDSQQAQHRRCSTSN (Figure 15B); at a concentration of 20-50 Mg / Kg weight dissolved in saline physiological solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy.

As shown in the graph, RANKL levels in osteoporotic rats at the start of treatment are increased by 155% compared to healthy control. At 90 days after the end of the treatment with the peptides object of this invention, a 305% increase in RANKL in serum of osteoporotic rats with respect to healthy control is shown. RANKL levels in osteoporotic Wistar rats treated with any of the peptides object of this invention show a 53% decrease compared to RANKL levels found in osteoporotic rats which received intraperitoneal injection of the pharmaceutical formulation consisting of solution as treatment. physiological saline for 90 days. These results indicate that treatment with any of the peptides, object of this invention inhibit the bone resorption process. Figure 18 corresponds to a graph the level of circulating osteoprotegerin (OPG) in serum extracted from Wistar rats at the beginning and at the end of the experimental period that was 90 days, after a period of 5 months of performing the ovariectomy. Osteoprotegerin levels were determined by ELISA assay (enzyme-linked immunosorbent assay), from the serum of 8 healthy Wistar rats, 8 ovanoectomized Wistar rats that received intraperitoneal saline physiological solution for 90 days as treatment. and 8 ovanoectomized Wistar rats osteoporotic agents treated with any of the peptides object of this invention derived from the root cement adhesion protein (HACD1 / CAP): AVIF (Figure 16A) or from the cement protein 1 (CEMP1): MGTSSTDSQQAQHRRCSTSN (Figure 16B); at a concentration of 20-50 pg / kg weight dissolved in saline physiological solution, and injected intraperitoneally, daily and for 90 days from 5 months after the ovariectomy. As seen in the graphs in Figure 16, serum osteoprotegerin levels in osteoporotic rats at the beginning of treatment decrease by 35% compared to healthy control. At 90 days after the treatment with the peptides object of this invention, an increase in circulating osteoprotegerin in serum is shown, which reaches levels similar to the healthy control with only a difference of 2%. The results indicate that the administration of any of the peptides, object of this invention, increases serum osteoprotegerin levels, which is interpreted as a regulatory role in bone metabolism by inhibiting the resorption process and promoting bone remineralization which is It reflects the increase in bone mineral density and the increase in the mechanical properties of bone tissue.

The results of the performance of the peptide of the invention show that for the control rat with osteoporosis, the absence of treatment does not prevent bone loss or the presence of empty spinal spaces in the femoral epiphysis, nor does it prevent bone resorption as observed in the 5 ^th lumbar vertebra accompanied by a reduction in the thickness of the cortical bone surrounding or covering the vertebral body. Likewise, and as a consequence the biochemical markers involved in the process of bone resorption and apposition present in the serum indicate that Alkaline Phosphatase and osteocalcin have high values with respect to normal as a consequence of the increase in bone resorption. Other markers such as osteoprotegerin and RANKL have decreased values compared to normal as a result of the increase in bone resorption. The formulation of AVIF peptide or IVfGTSSTDSQGAGHRRCSTSN peptide at a concentration of 20-50 pg / kg weight in combination with e! vehicle consisting of physiological saline solution presents the full spinal spaces without evidence of osteoporotic spaces, with normal bone microarchitecture. The biochemical markers of the bone resorption and apposition process present in serum show values similar to those obtained from healthy Wistar rats. Tissues examined histologically and presented in this invention show no difference in healthy controls and those obtained from Wistar rats treated with any of the peptides. In order to know the biodistribution of the peptides, the object of this invention were labeled using the technetium in the form of pertecnectate (TcO-f) - To make the marking the working solution was prepared, which contained: 40 ug of the peptides object of this invention, 50 ul of tartrate (2 mg / ml acetate buffer pH5), 10 p¡ of SnCl ₂ (2mg / ml HCL 0.1 N), 50 ul of gentisic acid (1 mg / ml) and 50 ul of 99mTc -NaTc04 ^" (5 mCi). Male Wistar rats weighing 250 g were used, which were at a temperature of 22 ° C, with a photoperiod of 12 hours and relative humidity at 50%, the feed and water was ad libiíum To evaluate the biodistribution, it was forming groups of three rats to which 40 μΙ of the labeled peptide were intraperitoneally injected, which were sacrificed with an anesthetic overdose at 30 ', 1, 3, 6 and 24 hours Samples of blood, heart, lung, liver, spleen, kidneys, stomach, small intestine, were collected. thick testis, muscle, bone, thyroid, brain and tooth. These organs were weighed on an analytical balance and subsequently placed in a Nal solid scintillation pit counter (TI) to detect the activity of each of the organs. With the above, e! percentage of the dose injected per grams of tissue (% D! / g). The results indicate that the AV1F peptide has the maximum value in the large intestine of 2.1% at 30 'decreasing its values to 0.3% at 24 hours. At the time of administration of the peptide, the organs where there was a greater presence of the peptide with a percentage of 2.1% were the liver and small intestine, decreasing to 0.8 and 0.08% of peptides at 24 hours respectively. In the kidney it reaches its maximum presence of 2.4% at 3 hours after injecting the peptide and decreases to 0.02% at 24 hours after being administered. This can be seen in Figure 17, graph (A) and in the biodistribution table of this peptide at the different times that were analyzed (B). The results indicate that at ios 30 'the MGTSSTDSQQAQHRRCSTSN peptide reaches a maximum level of 3.6% in the large intestine to decrease to levels of 0.006% at 24 hours. In the bone 1.3% and 1.4% are presented at 30 'and one hour respectively as maximum values decreasing at 24 hours to 0.4%. In the liver, the percentage of peptides in this organ reaches percentages of 3.4% when the peptide is injected, decreasing to! 0.2% at 24 hours. The kidney presents percentages of 1.8, 2.8 and 1.3, at 1, 3 and 8 hours respectively, decreasing the presence of the peptide at 24 hours to 0.9%. Therefore, these are the organs where the highest percentage of remaining peptide was determined. This can be seen in Figure 18, graph (A) and in the table with the percentages of presence of the peptide in the different organs examined (B).

The cytotoxic effect and the effect on cell proliferation was evaluated by means of the MU (tetrazolium) colorimetric assay [3 ~ {4,5-dimethylthazol-2-yl} -2,5-diphenyl tetrazoliumbromide], for 1, 2, 3 and 4 days Human osteoblasts derived from alveolar bone were seeded at a density of 1 x 10 ⁴ in 96-well plates. Cells were treated with peptides (independently) for 4 days with concentrations 1, 3 and 5 Mg / ml of each of the peptides. The medium was replaced daily and the peptides administered equally. The controls used were medium with fetal bovine serum a! 10% (positive control) and half with 0.5% bovine fetal serum (negative control.) The peptides were administered at the various concentrations contained in 0.5% medium. At the end of each treatment day 10 pL of the MTT solution (5mg / mL) was added to the wells and incubated for 3 hours. TO! after the supernatant was removed and the extraction was carried out by means of DfvISO for 1 hour at 37 ° G. The optical density of! supernatant was read in a reader for ELISA at 570 nm. The optical density reflects the number of living cells present in the culture. The results of Figure 19 A and B indicate that the administration of 5 pg of both peptides used independently promotes cell proliferation. The results indicate that the AVIFM peptide at a concentration of 5pg / mL at 4 days promotes proliferation by 82% compared to the positive control (10% fetal bovine serum) (A). The MGTSSTDSQQAQHRRCSTSN Peptide at a concentration of 5 pg / rnL promotes cell proliferation at 92% compared to the positive control (10% Bovine fetal serum) (B). These results indicate that the peptides, object of this invention promote cell proliferation and are not cytotoxic for human osteobites.

In figures 20 and 21 rnicrofotograffas of the histological section of a thickness of 5 pm and showing the critical size defect in Calvary of Wistar rats are presented. Letter (A) corresponds to the group that did not receive any treatment and after 16 weeks, it only shows the bridge of fibrous connective tissue without the formation of bone or indications of deposits of mineralized tissue. The letter (B) corresponds to a cut, after 16 weeks, of the control group treated only with scaffolding (Wistar rat) whose critical size defect was covered said three-dimensional scaffold based on gelatin (gelfoam sponge). No evidence of bone formation or tissue evidence mineralized. Only the presence of a bridge of fibrous tissue that joins the ends of the defect. The letter (C) corresponds to a cut after 16 weeks of the groups that received the three-dimensional scaffolding (gelatin sponge) formulation plus: 20-50 pg of the AVIFM peptide (figure 20) or 20-50 pg of the GTSSTDSQQAQHR CSTSN peptide (Figure 21), left in situ in the critical size defect in Wistar rat calvary. You can see that e! 100% of the defect has been filled with material with histomorphological characteristics of bone tissue with normal characteristics.

Once the peptides of the invention have been evaluated, comparing them with recombinant proteins and peptides commonly used in therapeutics to achieve bone repair and / or regeneration such as parathyroid hormone (PTH) parathyroid hormone-related protein (PTHrP), Matrices of amphiphilic peptides, peptides derived from BMP7 (BFP4) and B P2, the biologically active peptides, object of this invention also exhibit the following advantages:

1) They perform a function similar to a polypeptide (either recombinant or natural protein) and the active sites of this short chain of amino acids (the peptide) can be fully exposed and can bind to their corresponding receptor on the cell surface to achieve a Better bioactivity Our experimental results clearly demonstrate that any of the peptides described in this invention and at a concentration of 20-50 pg promote the deposition of calcium phosphate salts in the form of hydroxyapatite and promote the self-assembly of these crystals during the mineralization process in vitro (see the results experienced in Figures 1 and 2) 2) These are small peptides since their composition is less than 100 amino acids. Small peptides composed of less than 50 amino acids can be easily synthesized artificially. However, the synthesis of peptides greater than 50 amino acids is difficult and therefore they are expressed through genetic engineering. Compared to the production of recombinant proteins, small peptides exhibit a smaller structure and are easier to produce on larger scales. Therefore, the economic impact on patients suffering from osteopenia, and osteoporosis, or who have suffered loss of bone mass, which requires regeneration; It is significantly reduced due to the low production cost of the peptide.

3) Due to the relatively small molecular mass of the peptides, the therapeutic formulation is more abundant so that e! Peptide can be dissolved in solution and injected subcutaneously or placed in situ. The novel aspects that are considered characteristic of the present invention are set forth in particular in the appended claims. However, the invention itself, both for its structural organization, together with other objects and advantages thereof, will be better understood in the following statements that define the object of the invention and its scope:

The present invention provides a peptide consisting of the last five amino acids of the carboxyl terminal of the root cement adhesion protein (HACD1 / CAP) with the sequence AVSFM: SEQ ID NO: 1, with hydroxyapatite crystal nucleating properties , osteogenic and osteinductive. The present invention provides a peptide derived from the terminus! Cement 1 protein amino (CEMP1) consisting of 20 amino acids, with the sequence MGTSSTDSQQAQHRRCSTSN: SEQ¡D NO: 2, with nucleating properties of hydroxyapatite, osteogenic and osteinductive crystals.

Both peptides possess intrinsic biological activity to increase bone mineral density, recovery of bone microarchy, to promote the osteogenesis process, inhibit bone resorption, increase bone mineral density and therefore as an effective method for recovery of physical characteristics. - Bone mechanics and clinically effective for the treatment of osteoporosis.

It is yet another object of the present invention, to provide a pharmaceutical composition comprising any of the administrable peptide sequences at a concentration of 20-50 pg / kg of weight, combined with a pharmaceutically acceptable carrier, carrier, or excipient, and which they are useful for the treatment of osteopenia, osteoporosis and bone regeneration in in vivo systems,

The pharmaceutical formulation or composition of Sa invention is basically characterized in that it comprises the following components:

 a) the peptide derived from root cement adhesion protein

(HACD1 / CAP) and consisting of 5 amino acids: AVIF,

b) and / or the Peptide derived from cement propellant 1 (CEMPI) and consisting of 20 amino acids: MGTSSTDSQQAQHRRCSTSN. Part of the embodiments of the invention relate to pharmaceutical formulations whose active ingredient is the AVIFfvl peptide or the peptide MGTSSTDSQQAQHRRCSTSN which are in combination with a framaceutically acceptable vehicle or excipient, including for example a physiological saline solution pH 7.4 or a phosphate buffer solution pH 7.4. This formulation has the profile of activities necessary to counteract the problems raised, but other formulations can be used.

It is yet another object of the present invention, to provide a pharmaceutical composition comprising the AVIF1VI peptide or the MGTSSTDSQQAQHRRCSTSN peptide which is found in combination with a synthetic or natural three-dimensional scaffolding that can be a collagen, elastin, fibrin, hyaluronic acid polymer , chitosan / chitin or alginate, for example it can also be a scaffold shaped like a sponge composed mainly of gelatin, and which are useful in the repair and / or regeneration of bone in in vivo systems. Modalities of the invention are the uses of any of the peptides alone or in combination to promote the deposition of calcium phosphate salts in the form of hydroxyapatite or in vitro system in grafts conditioned in a suitable medium, or in an in vivo system. , that is, in vertebrates in general but particularly in mammals and more specifically in humans who suffer from osteoporosis (osteopenia) or who already suffer from osteoporosis, which results in a decrease in bone mineral density, loss of bone substance, decreased mechanical resistance to fracture and alterations in protein levels associated with bone metabolism. Therefore, the pharmaceutical formulation that is the reason for this invention and as detailed below is capable of reversing all these alterations, at any stage of the condition, and serving as an effective treatment for osteoporosis in living beings. The peptides, object of the invention, can be used in humans and vertebrate animals to treat any condition where it is required to promote the osteogenesis process, inhibit bone resorption, increase bone mineral density, for the treatment of osteoporosis and regeneration. Bone in vivo. Likewise and due to the biological properties that peptides possess and experimentally demonstrated in vitro and in vivo they can be used for the regeneration of other mineralized tissues such as enamel and dentin and be used as preventive therapeutic agents for the development of diseases. Bones such as osfeopenia, osteoporosis, and osteoarthritis and to prevent and treat fractures that occur in diseases such as osteogenesis imperfecta.

Examples of application of the peptide of the invention for the correction of bone defects are: its administration after the insertion of an autograft or allograft, of bone bridges or for bone fusion; Bone regeneration is also required for treatment of periodontitis or its consequences. It should be mentioned with respect to bone bridges, these are used to eliminate joint movement, this is a strategy to treat degenerative disorders in the spine and joints, however, up to 45% of spine surgeries errors occur in the spinal fusion, leaving the patient with permanent pain and susceptible to repeated surgeries with unsuccessful results, so that the present invention also provides a therapeutic alternative for this condition.

Peptides can be solubilized, prepared and also used to decrease and inhibit the effects of osteoclastogenesis and osteocystic activity in diseases in which bone fractures occur. It is within the scope of the invention to be able to use the peptides in the doses that the attending physician decides adjust according to the patient's condition, and may be a preferred dose! in a range of 20-50 pg / kg of weight. It remains inside! scope of the invention the possibility of using the combined peptides for the treatment of patients, according to the criteria of the attending physician.

Examples of other conditions that the patient to present with the peptides of the invention may present include: Paget's disease, cancers that can metastasize to bone and induce fracture (eg, multiple myeloma, breast cancer, some melanomas and cancers that do not metastasize to bone, but result in hypercaicemia and loss of bone matrix (such as squamous cell carcinomas), to name a few, that fall within the scope of the invention.

Peptides can be synthesized by conventional methods such as So are the Merrifieid technique, the Sheppard technique, by support or solid phase (FMOC), etc. with adequate yields for industrial scale.

Although certain embodiments of the invention have been illustrated and described, it should be emphasized that numerous modifications to it are possible, but such modifications would not represent a departure from the true scope of the invention. Therefore, the present invention should not be considered as restricted except as set forth in the prior art, as well as by the scope of the appended claims.

In conclusion, the experimental results presented here, with this experimental model indicate that the peptides, object of this invention are capable of promoting bone remineraiization and do not present harmful side effects, which ensures viability as a safe therapeutic method for the treatment of osteoporosis and bone regeneration in vivo.

The present invention will be better understood from the following examples, which are presented for illustrative purposes only to allow a full understanding of the preferred embodiments of the present invention, without implying that there are no other non-illustrated modalities that can be implemented based on the detailed description above. EXAMPLES

 Example 1. Moderate in adult Wistar rats demonstrating the use of peptides for e! Osteoporosis treatment.

The peptides with the sequences AVIFM and MGTSSTDSGQAQHRRCSTSN have been artificially synthesized, and resuspended in a vehicle consisting of physiological saline solution pH 7.4 that is inoculated intraperitoneally and / or subcutaneously that was used to increase bone mineral density and recovery of bone microarchitecture , of the physico-mechanical and biological properties in an experimental model of Wistar rats (Rattus norvegicus) ovarioectomízadas and that they attend with osteoporosis. 48 female rats of the Wistar strain, 3 months old, weighing 250 ± 20 gr were used. The animals were acclimatized for 14 days at an ambient temperature of 22 ° C, with a 12-hour photoperiod and 50% relative humidity, the food and water was ad iibitum. The rats were sedated with acepromycin maleate (Relax 0.5g / 100mi) at a dose of 20 mg / kg of weight and as a general anesthetic tiletamine and zoiazepam were used at a concentration of 25 mg / kg of weight. AND! Anesthetic maintenance was with constant flow of isoflurane. Once anesthetized the Rats proceeded to perform the bilateral ovariectomla procedure for which the already anesthetized rat was placed lateral decubitus, shaved from the last rib forming a rectangle of approximately 4x3 cm. This area was disinfected with an electrolyzed solution of superoxidation with neutral pH (Veteribac). Subsequently with a scalpel a linear incision of approximately 2 cm was made until reaching the muscle and exposing the abdominal cavity, with great care the cervix was located and identified, it was ligated right in the middle area with 8/0 polyglycolic acid suture and later with the scalpel, Sos ovarios were removed. It was sutured by planes (abdominal muscles and skin) with 4/0 polyglycolic acid and finally the surgical area was cleaned with hydrogen peroxide. The rats were kept in bioterium conditions for 5 months at 12 hours of light and 12 hours of darkness, at an average temperature of 22 ° C with food and water ad Iibitum. The surgical group did not have any surgical procedure and they remained in identical conditions to the ovarioecíomized rats. Once this period ended, 32 ovarioectomized rats were divided into 4 groups of 8 rats each. One group was injected intraperitoneally with the AVIFiVI peptide and another group with the MGTSSTDSQQAQHRRCSTSN peptide both resuspended in physiological saline solution at pH 7.4 and at a concentration of 20-50 pg / kg of weight for 90 days. The control group of osteoporotic rats (16 rats) was treated with physiological saline solution pH 7.4 for 90 days. The healthy control group of (16) rats received no treatment. Blood was obtained from all groups of rats at the beginning and end of treatment (90 days). 5 ^th dorsal vertebrae of the rats was analyzed by means of computed tomography (μΟΤ) prior to euthanasia with CO? on day 90 of treatment. At the end, the femurs and the 5 ^ts dorsal vertebra were obtained and fixed in 10% paraformaldehyde and embedded in paraffin and histological cuts of 5 μηι thick and stained with Masson's Trichrome stain were made for examination in the light microscope . The histological examination presented in Figure 3C or 4C of the epiphysis of the femur reveals that the groups that received e! treatment with the AVIF peptide or the GTSSTDSQQAGHRRCSTSN peptide there is a presence of bone marrow between the cortical spaces and the bone trabecuiated forms a network structure similar to the microarchitecture that presents the healthy conirol group (panels A and C of Figures 7 and 8). In contrast to osteoporotic rats without treatment with any of the peptides where there is a decrease in bone cortical thickness and the medullary spaces occupied by fatty tissue (panels B of Figures 7 and 8). Likewise, this histological pattern in the transverse and sagittal planes reveals the uniform bone trabecuous ye! filling the spaces with bone marrow Rtertrabeculares body 5 ^th lumbar vertebra where the healthy and osteoporotic conírol Raias who were treated with I peptides of the invention show similar characteristics in their repeated tisuiar microarquitecíura. Osteoporotic rats revealed that the medullary spaces are occupied by fatty tissue and decreased trabecular bone framework. In addition to the histologically described mechanical resistance analyzes as seen in Figure 12, the osteoporotic rats treated with any of the peptides, object of this invention have similar values with healthy control rats of compression resistance, while osteoporotic raias without treatment with any of the peptides exhibit a significant difference from healthy control.

Also, the analyzes of the biochemical markers show that the treatment of osteoporotic rats with any of the peptides shows serum levels similar to the healthy control. Example 2. Bone regeneration that occurs due to the presence of the peptides with the AVIFM or MGTSSTDSQQAQHRRCSTSN sequences. These peptides have been artificially synthesized, and then combined with a three-dimensional scaffold based on gelatin (gelatin sponge), so it was used for the regeneration of critical-sized bone defects in an animal model: Groups of 14 male Wistar rats of approximately 250 grams of weight. The anesthesia of the rats was carried out by means of intraperioneal injection of ketamine. The critical size defect was made by means of a 3 cm incision in the calvate and a mucoperiosteal flap was lifted. Subsequently, with a 9 mm trephine, the defect was performed in the rat's bone baldness. The formulation consisting of a 9 mm diameter disc, porous three-dimensional, was implanted in the experimental group! based on gelatin (Gelfoam) containing the peptide at a concentration of 20-50 Mg / disk. Previously, the three-dimensional scaffolding (gelatin sponge) was incubated with a concentration of the corresponding peptide 20-50 Mg / gelatin sponge disk and dried under vacuum. The control animals were treated only with a jelly sponge disk and the resuspension vehicle of! peptide (phosphate buffer pH 7.4) and another group remained untreated. The blood supply to the surgical site is secured. The operation site was sealed with Satin S-100, whose content is mainly gelatin. At the end of 18 weeks, the tissues were fixed with 10% formaldehyde and embedded in paraffin and histological sections of 5 pm thick were made and stained with asson trichrome staining for examination under the light microscope. Histomorphometric analyzes were performed to determine the amount of mineralized tissue formed in the critical size defect in the Calvary of Wistar rats. The histological examination is presented in Figures 20 and 21 for the sequences AVIFM and GTSSTDSQQAQHRRCSTSN which reveal that in the group that received only three-dimensional Gelfoam the process of osteogenesis was not carried out, nor formation of osteoid material associated with degradation complete and absorption of the vehicle (jelly sponge), as can be seen in the letter A of figures 20 and 21 respectively, as well as in e! untreated group, as can be seen in (B) of figures 20 and 21 respectively. Whereas in the groups that received the formula either of the AVIFM peptide or of the GTSSTDSQQAQHRRCSTSN peptide in conjunction with the three-dimensional gelatin sponge scaffold a 100% repair was carried out on e! filling of the defect (with bone) as clearly observed in (C) of figures 20 and 21 respectively.

Example 3. Manufacture of three-dimensional scaffolds for preclinical models.

The three-dimensional scaffolding used in this invention is based on a jelly sponge commercially called Geifoam®, which is absorbable and sponge-like jelly. In this invention, gelatin discs 9 mm in diameter and 2 mm thick were cut. This three-dimensional gelatin sponge was embedded with the AVIFM peptide or the MGTSSTDSQQAQHRRCSTSN peptide respectively, previously diluted in sterile saline solution at a concentration of 20-50 pg of any of the peptides, object of this invention and the three-dimensional scaffolding containing the peptide, in a desiccator at a temperature of 4 ° C for one hour. The three-dimensional disk-shaped scaffold was irradiated with ultraviolet light for 24 hours and used immediately to cover the critical size defect in Wistar rat calvary.

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Claims

1. - The osteogenic peptide selected from the group consisting of: AVIFM peptide identified as SEQ ID NO: 1 and MGTSSTDSQQAQHRRCSTSN peptide identified as SEQ ID NO: 2 and possible variants thereof that retain their osteogenic activity.

2. - Use of an osteogenic peptide selected from! group consisting of: AVIFM peptide identified as SEQ ID NO: 1 and GTSSTDSQQAQHR CSTSN peptide identified as SEQ ID NO: 2, to prepare a pharmaceutical composition for:

 to. Promote osteogenesis and / or

 b. Increase bone mineral density and / or

 C. Promote bone regeneration in vivo in vertebrates, including humans.

3 - The use according to claim 2 wherein the osteogenesis involves the regulation and in situ promotion of the deposition of calcium and phosphorus salts, nucleation of hydroxyapatia crystals and their self-assembly during the mineralization process in conditions where it is required. Bone neoformation.

4 - The use of an osteogenic peptide selected from the group consisting of: AVIFM peptide identified as SEQ ID NO: 1 and MGTSSTDSQQAQHRRCSTSN peptide identified as SEQ ID NO: 2, according to claim 1, 2 6 3, to prepare a pharmaceutical composition to prevent or treat osteoporosis.

5 - The use of an osteogenic peptide selected from the group consisting of: AVIFM peptide identified as SEQ ID NO: 1 and IV! GTSSTDSQQAQHRRCSTSN peptide identified as SEQ ID NO: 2, in accordance with claim 1, 2 or 3, for Prepare a pharmaceutical composition to promote bone regeneration.

6. - A pharmaceutical composition characterized in that it comprises a! minus one of the peptides selected from the group consisting of: AVIFM peptide identified as SEQ ID NO: 1 and SvIGTSSTDSQQAQHRRCSTSN peptide identified as SEQ ID NO: 2, and a pharmaceutically acceptable carrier, excipient or diluent, including a pharmaceutically acceptable natural or synthetic polymer .

7. The composition according to claim 8, characterized in that the excipient or diluent of the AVI FM peptide identified as SEQ ID NO: 1 or of the fvIGTSSTDSQQAGHRRCSTSN peptide identified as SEQ ID NO: 2, is phosphate buffer solution pH 7.4 and the Polymer is made of collagen, elastin, fibrin, hyaluronic acid, chitosan / chitin or alginate.

8. The composition according to claims 6 6 7, characterized in that the AVIFM peptide identified as SEQ ID NO: 1 or the MGTSSTDSQQAQHRRCSTSN peptide identified as SEQ ID NO: 2, is administrable in a concentration preferably at a dose of 20 ug / Kg of weight for the treatment of osteoporosis and bone regeneration.