WO2019176693A1 - Inhibiteur de l'expression du facteur lié à la formation osseuse ou au facteur lié à la calcification dans un tissu extrasquelettique - Google Patents

Inhibiteur de l'expression du facteur lié à la formation osseuse ou au facteur lié à la calcification dans un tissu extrasquelettique Download PDF

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Publication number
WO2019176693A1
WO2019176693A1 PCT/JP2019/008900 JP2019008900W WO2019176693A1 WO 2019176693 A1 WO2019176693 A1 WO 2019176693A1 JP 2019008900 W JP2019008900 W JP 2019008900W WO 2019176693 A1 WO2019176693 A1 WO 2019176693A1
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calcification
related factor
expression
ossification
phytic acid
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PCT/JP2019/008900
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English (en)
Japanese (ja)
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裕二 吉子
朋子 南崎
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国立大学法人広島大学
株式会社ラフィーネインターナショナル
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Priority to JP2020506438A priority Critical patent/JPWO2019176693A1/ja
Publication of WO2019176693A1 publication Critical patent/WO2019176693A1/fr
Priority to JP2023133764A priority patent/JP2023144116A/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates

Definitions

  • the present invention relates to an expression inhibitor of bone formation-related factor or calcification-related factor in extra-bone tissue.
  • the cells that constitute bone include osteoblasts, bone cells, and osteoclasts.
  • Osteoblasts are osteogenic cells differentiated from mesenchymal stem cells and gradually differentiate from stem cells.
  • marker genes that serve as indicators of the differentiation stage of cells show various patterns. For example, in the early stage of proliferation, CCND1 and HDAC, which are proteins that control the cell cycle, are expressed, but differentiation traits are expressed in a time-dependent manner, and COL1A1 is expressed early in differentiation. Then, as it matures, it shows expression patterns in the order of FN1, ALPL, IBSP, and BGLAP. Among these markers, COL1A1 and ALPL are expressed independently of the cell cycle, while BGLAP is expressed after the end of cell division.
  • RUNX2 plays an important role in the production of bone matrix proteins because it promotes transcription by binding to cis elements upstream of the BGLAP and SPP1 genes.
  • ectopic ossification a phenomenon in which pathological bone formation occurs in a site where bone tissue is not originally formed, occurs in addition to normal skeleton formation.
  • calcification is a general term for the deposition of calcium, and the phenomenon in which pathological calcification occurs in areas that are not originally calcified is called ectopic calcification, but at least part of this ectopic calcification is It is known that it occurs by the same molecular mechanism as bone formation (Non-patent Document 1). Tissues with ectopic ossification and ectopic calcification cause various disorders.
  • the joint region is accompanied by a limited range of motion, which significantly reduces the quality of life (QOL).
  • QOL quality of life
  • Patent Document 1 focused on the fact that Nrf2 can suppress Bglap transcriptional activity in a Runx2-dependent manner, and thus negative regulation of bone / cartilage differentiation by nrf2 can be attributed to inhibition of Runx2 by NRF2.
  • a regulator of osteoblast differentiation has been described.
  • Patent Document 1 do not sufficiently suppress the expression of bone formation-related factors or calcification-related factors.
  • the present invention has been made in view of such problems, and an object of the present invention is to provide a novel inhibitor of the expression of osteogenesis-related factors or calcification-related factors in extra-osseous tissue.
  • the expression inhibitor of osteogenesis-related factor or calcification-related factor in extra-bone tissue according to the present invention is characterized by containing phytic acid.
  • FIG. 1 It is a diagram showing the effect of phytic acid administration in a calcification model of mouse aortic organ culture under 2.6 mM phosphate (Pi) load environment, of which (A) is a photographic diagram of thoracic aortic organ culture removed from the mouse, (B) is a micro-CT image showing the effect of phytic acid administration on calcification of mouse aorta cultured under Pi load environment, (C) is for calcification of mouse aortic organ cultured under Pi load environment It is a graph which shows the effect of phytic acid administration.
  • A is a photographic diagram of thoracic aortic organ culture removed from the mouse
  • B is a micro-CT image showing the effect of phytic acid administration on calcification of mouse aorta cultured under Pi load environment
  • C is for calcification of mouse aortic organ cultured under Pi load environment
  • FIG. 1 It is a figure showing the inhibitory effect of warfarin-induced arterial calcification by phytic acid, of which (A) is a photograph of a negative control blood vessel to which only vitamin K1 was administered, (B) is a lime after adding warfarin administration (C) is a photograph showing a state in which calcification is suppressed when phytic acid is further administered at 2 mg / 50-120 g body weight / day. It is a figure which shows the serum calcium density
  • Phytic acid is a substance represented by the following structural formula, and is a component that is abundant in unrefined grains and beans and exhibits a strong chelating action on minerals.
  • various physiological functions including an antioxidant action can be expected, and many uses as functional ingredients are also disclosed.
  • phytic acid has an effect of suppressing the expression of bone formation-related factors or calcification-related factors in extra-bone tissue.
  • the expression inhibitor of osteogenesis-related factor or calcification-related factor in extra-bone tissue according to the present invention is characterized by containing phytic acid.
  • Phytic acid can also be used as a phytate and is not particularly limited. Examples thereof include calcium salt, magnesium salt, and zinc salt of phytic acid.
  • the expression inhibitor of osteogenesis-related factor or calcification-related factor in extra-bone tissue contains phytic acid as a pharmaceutically effective amount.
  • phytic acid for example, tablets, granules, fine granules, capsules
  • preparations for oral administration such as agents, various liquid preparations suitable for oral administration, or preparations for parenteral administration such as injections and suppositories.
  • preparations for injection are prepared, for example, in the form of solutions, emulsions or suspensions, and are made isotonic with blood.
  • Formulations in the form of liquids, emulsions or suspensions are prepared using, for example, an aqueous medium, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester .
  • the aqueous medium include water or a medium containing water.
  • sterilized water is used.
  • the medium containing water include physiological saline, PBS (phosphate buffered physiological saline), lactic acid-containing Ringer's solution, and the like.
  • the content of phytic acid or a salt thereof is not particularly limited, but is, for example, 1 ⁇ g / mL to 10 ⁇ g / mL, preferably 100 ⁇ g / mL to 1 ⁇ m mg / mL.
  • additives usually used in the art can be appropriately used.
  • the additive include isotonic agents, stabilizers, buffers, preservatives, chelating agents, antioxidants, and solubilizing agents.
  • the isotonic agent include sugars such as glucose, sorbitol and mannitol, sodium chloride, glycerin, propylene glycol, polyethylene glycol and the like.
  • the stabilizer include sodium sulfite.
  • the buffer include borate buffer, phosphate buffer, citrate buffer, tartaric acid buffer, and acetate buffer.
  • Examples of the preservative include paraoxybenzoic acid ester, benzyl alcohol, chlorocresol, phenethyl alcohol, benzethonium chloride and the like.
  • Examples of chelating agents include sodium edetate and sodium citrate.
  • Examples of the antioxidant include sodium sulfite, sodium hydrogen sulfite, sodium ascorbate, sodium thiosulfate and the like.
  • Examples of the solubilizer include dextran, polyvinylpyrrolidone, sodium benzoate, ethylenediamine, salicylic acid amide, nicotinic acid amide, polyoxyethylene hydrogenated castor oil derivative, and the like.
  • the pH preparation may be contained in the injectable preparation.
  • the pH adjuster may be an acid or a base.
  • the acids include ascorbic acid, hydrochloric acid, gluconic acid, acetic acid, lactic acid, boric acid, phosphoric acid, sulfuric acid, tartaric acid, and citric acid.
  • the base include potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, diethanolamine, triethanolamine and the like.
  • the bone formation-related factor is not particularly limited, and examples thereof include ALPL, BGLAP, RUNX2, SP7 (Osterix), DLX5, and the like.
  • the bone mineralization-related factor is not particularly limited, and examples thereof include SLC20A1, SLC20A2, ENPP1, ALPL, and SPP1.
  • the action of phytic acid suppresses the expression of bone formation-related factors or calcification-related factors in extra-osseous tissue, thereby suppressing, for example, ectopic ossification and also suppressing ectopic calcification. be able to.
  • Ectopic ossification mainly includes post-traumatic ossification, neoplastic ossification, and ossification in a neurological state.
  • Post-traumatic ossification is ossification that occurs at the attachment of the medial collateral ligament of the femoral endocondyle after a major trauma or a small traumatic trauma.
  • Neoplastic ossification is soft tissue ossification that occurs at the time of paraskeletal osteosarcoma, soft tissue osteosarcoma, intramuscular hemangioma and the like.
  • Osteogenesis in the neurological state is ossification that occurs in the paralyzed limbs due to paraplegia or limb paralysis due to spinal cord injury or hemiplegia due to stroke.
  • Progressive ossifying fibrodysplasia is a disease in which skeletal malformations and soft tissue ossification are observed systemically.
  • the ectopic calcification mainly includes metastatic calcification, dystrophic calcification, and idiopathic calcification.
  • Metastatic calcification is calcification that occurs because there is one or both of long-lasting hypercalcemia and hyperphosphatemia.
  • Heterotrophic calcification is calcification in which calcium salt deposits occur in soft tissues without any disturbance of calcium or phosphorus metabolism.
  • Idiopathic calcification is a major humerus nodule, especially supraspinatus attachment, deltoid muscle attachment, calcific tendonitis or bursitis that occurs frequently on the outer epicondyle of the knee joint, cartilage calcification, It is localized calcification and pandemic calcification.
  • Ectopic calcification is partly due to the same molecular mechanism as ectopic ossification, and bone-like tissue formation occurs in areas where bone tissue does not originally exist, that is, muscle, fascia, ligament, joint capsule, blood vessels, etc. It is a phenomenon.
  • Specific diseases include renal disease, vascular calcification associated with dialysis, vascular calcification due to arteriosclerosis, infant systemic arterial calcification (GACI), progressive ossifying fibrodysplasia (FOP), posterior longitudinal ligament Designated intractable diseases such as ossification disease (OPLL) or yellow ligament ossification disease are applicable.
  • the prophylactic and / or therapeutic agent for ectopic ossification or ectopic calcification resulting from expression of an osteogenesis-related factor or calcification-related factor according to the present embodiment is characterized by containing phytic acid.
  • the disease causing ectopic ossification is not particularly limited, and includes FOP, OPLL, or ossification of the ligamentum flavum mentioned in the above specific examples.
  • FOP is a genetic disease characterized by congenital malformations of the thumb and progressive ectopic ossification.
  • FOP may be accompanied by gene mutation, for example, ACVR1 mutation.
  • FOP results in extra-articular stiffening or thorax fusion of the main joints in the mid-axis skeleton and appendage skeleton, resulting in severe disability and respiratory failure.
  • the disease causing ectopic calcification is not particularly limited, and includes renal disease or vascular calcification associated with dialysis, vascular calcification due to arteriosclerosis, or GACI mentioned in the above specific examples.
  • prevention includes suppressing and delaying the onset of a disease, and includes not only prevention before becoming a disease but also prevention of recurrence of the disease after treatment.
  • treatment includes curing a symptom, improving the symptom, and suppressing the progression of the symptom.
  • the dosage of the prophylactic and / or therapeutic agent for ectopic ossification or ectopic calcification resulting from the expression of an osteogenesis-related factor or calcification-related factor according to this embodiment can be appropriately changed.
  • the amount is about 0.1 to about 2000 mg / kg / day, preferably about 1 to 200 mg / kg / day, and this amount can be administered once a day or divided into 2 to 3 times.
  • Example 1 Effect of intravenous administration of phytic acid in a BMP-2-dependent intramuscular ossification model
  • Atelocollagen impregnated with BMP-2 was transplanted into the greater gluteus muscle of 4-week-old ddY male mice.
  • An ectopic ossification model in which ossification was observed in the transplanted part over the week was created.
  • the ossified tissue of the ectopic ossification model was confirmed in the micro CT image.
  • osmotic pump Alzet
  • 0.08 mg / body / day, 0.4 mg / body / day or 2 mg / body / day sodium phytate was continuously administered from the right jugular vein to confirm the effect on ectopic ossification. did.
  • the amount of ossified tissue decreased depending on the dose of phytic acid.
  • the vertical axis represents the bone mass (mm 3 ) obtained by micro CT.
  • Matrix mineralization including bone matrix
  • matrix vesicles produced and secreted by osteoblasts present on the bone surface (matrix vesicular calcification) and formed inside the matrix vesicles
  • matrix vesicular calcification matrix vesicular calcification
  • the formed calcium phosphate crystal mass shows a ribbon-like or needle-like shape, and when it breaks the membrane of the vesicle and is exposed to the outside, it forms a spherical aggregate (mineralized nodule), and then the surrounding collagen By contacting the fine fibers, calcification is spread to the collagen fibers.
  • osteoblasts are cells responsible for bone formation and induce calcification.
  • Example 3 Calcified tissue staining diagram of mouse aortic organ culture at phosphate loading
  • 4% paraformaldehyde PBS was used after completion of the culture.
  • a paraffin specimen was prepared by fixing. 5 ⁇ m sections were prepared and Kossa staining was performed. Note that Kossa staining is a staining method used when detecting lime (calcium salt) deposited in histological examination, and stains calcium phosphate salt, calcium carbonate salt and the like in black by the action of silver nitrate.
  • the scale bar is 25 ⁇ m.
  • Example 4 Tissue staining diagram of osteoblast marker Using the above paraffin section for the mouse aorta organ culture model under phosphate-loaded environment in Example 2 above, immunization of osteoblast (bone formation) marker ALP Staining was attempted.
  • ALP alkaline phosphatase
  • BAP bone formation marker
  • the immunostaining was observed using a fluorescence microscope after reacting with an anti-ALP antibody and Alexa594-labeled secondary antibody according to a conventional method.
  • DAPI was used as a counterstain.
  • FIG. 4 when phosphate was loaded, ALP, which is an osteoblast marker, was stained red when only the solvent was used. On the other hand, depending on the dose of phytic acid, it is understood that the portion stained red is reduced, and the formation of osteoblast-like cells is suppressed.
  • the scale bar is 75 ⁇ m.
  • Example 5 Expression of Osteoblast Marker Gene
  • the expression of osteoblast (bone formation) marker gene in the mouse aorta organ culture model under the phosphate load environment in Example 2 above was examined by RT-PCR method. It was. After completion of the culture, RNA was extracted according to a conventional method, and after cDNA preparation, gene expression was quantified by real-time PCR. As osteogenesis-related factors, the expression of Alpl, Runx2, and Bglap was examined.
  • the Alpl gene is a gene encoding a tissue non-specific isozyme (TNSALP) of Alkaline phosphatase.
  • Runx2 is a transcription factor essential for osteoblast differentiation and chondrocyte late differentiation.
  • Bglap is a marker that confirms the direction of differentiation from mesenchymal stem cells to osteoblasts because it is expressed at a high level when cultured cells are calcified later in differentiation.
  • Slc20a1 expression was examined as a calcification-related factor.
  • SLC20A1 is a type III phosphate transporter and is known to play an important role in calcification.
  • An increase in the phosphate concentration in the blood causes calcification of vascular smooth muscle and causes arteriosclerosis centering on calcification of the media. This is because the increase of extracellular phosphate concentration increases the intracellular influx of phosphate via SLC20A1 in vascular smooth muscle cells, induces the expression of osteoblast differentiation-related proteins, and differentiates into osteoblast-like cells It is thought that calcification is caused.
  • FIGS. 5 (A), (B) and (C) it was shown that the expression of osteogenesis-related factors was suppressed in the presence of phytic acid.
  • FIG. 5 (D) it was shown that the expression of calcification-related factors was suppressed in the presence of phytic acid.
  • Example 6 Inhibition of Warfarin-Induced Arterial Calcification Vitamin K inhibitors typified by warfarin inhibit matrix GIA protein (MGP) Gla formation, which is one of calcification inhibitory factors, and There is an inhibitory effect.
  • MGP matrix GIA protein
  • the normal diet was switched to a high phosphate diet containing 1.2 wt% phosphate and 0.6 wt% calcium, and the mother rat was given a high phosphate load.
  • oral administration of vitamin K1 1.5 mg / 100 g body weight / day
  • sodium phytate 0.4 and 2 mg / 50-120 g body weight / day
  • Example 7 Fluctuation of serum calcium (Ca) and phosphate (inorganic phosphate, Pi) concentration in intravenous administration of phytic acid Using an osmotic pump as described above in the vein of a 4-week-old ddY male mouse Then, phytic acid was continuously administered for 1 week, and changes in calcium concentration in blood were measured. The doses of phytic acid were 0.08 mg / body / day, 0.4 mg / body / day, and 2 mg / body / day. The Ca concentration was measured with Calcium E TM Test Wako. The results are shown in FIG. As shown in FIG. 7, the Ca concentration in serum was not affected by phytic acid. Similarly, the serum Pi concentration was measured by Phospha C-Test Wako. The results are shown in FIG. As shown in FIG. 8, phytic acid had no effect on serum Pi concentration.
  • Ca calcium
  • phosphate inorganic phosphate, Pi
  • Example 8 Inhibition of calcification in Enpp1 mutant mice Enpp1 is a gene responsible for ossification of the posterior longitudinal ligament, and many infant systemic arterial calcifications involve both allelic mutations of the same gene.
  • a high phosphorus diet was fed to the mother mice of Enpp1 mutant newborn mice (C57BL / 6J-Enpp1 asj / GrsrJ), and a high phosphorus diet was fed directly after weaning at 3 weeks of age.
  • FIG. 9 shows an arterial arch.
  • (A) is Vehicle
  • (B) is 0.4 mg / body / day
  • (C) is 0.04 mg / body / day.
  • phytic acid almost completely suppressed vascular calcification stained with alizarin red at a concentration of 0.04 mg / body / day or more.
  • Example 9 Measurement of bone morphology by micro CT The bone morphology of the proximal end of the tibia was measured for the Enpp1 mutant mouse (6 weeks old) of (8) above. Cortical bone and sea surface bone were analyzed for bone mass, bone mass / tissue mass, bone density, number of sea surface bones, sea surface bone thickness, and the like. The bone mass and bone density are shown in FIG. Among them, (A) is cortical bone mass, (B) is sea surface bone mass, (C) is cortical bone density, and (D) is sea surface bone density. None of the parameters was affected by phytic acid administration. Similarly, even when phytic acid was administered to normal mice, no abnormality was observed in various bone morphometry parameters.
  • Example 7 Serum sample obtained from the mouse of Example 7 (continuous intravenous administration for 1 week)
  • Serum sample administered with 0.4 mg / body / day sodium phytate and vehicle in Example 8 discontinuous intravenous administration for 2 weeks
  • FIG. 11 shows the results of serum samples administered with 0.4 mg / body / day of sodium phytate and vehicle, in which (A) is the serum zinc concentration and (B) is the serum iron concentration.
  • phytic acid suppresses ectopic ossification or ectopic calcification, but its main mechanism of action is not the chelating effect of phytic acid, but an osteogenesis-related factor or calcification. It can be considered that the expression of related factors is suppressed.

Abstract

L'invention concerne un inhibiteur de l'expression d'un facteur lié à la formation osseuse ou d'un facteur lié à la calcification dans un tissu extrasquelettique. Un inhibiteur de l'expression d'un facteur lié à la formation osseuse dans un tissu extrasquelettique, l'inhibiteur étant caractérisé en ce qu'il comprend de l'acide phytique. Le facteur lié à la formation osseuse est l'un quelconque parmi ALPL, RUNX2, BGLAP et analogues. Un inhibiteur de l'expression d'un facteur lié à la calcification dans un tissu extrasquelettique, l'inhibiteur étant caractérisé en ce qu'il comprend de l'acide phytique. Le facteur lié à la calcification est l'un quelconque parmi SLC20A1, SLC20A2, ENPP1, ALPL, SPP1 et analogues. Ces inhibiteurs peuvent empêcher une ossification hétérotopique et une calcification ectopique, respectivement, lorsqu'ils sont administrés par voie intraveineuse.
PCT/JP2019/008900 2018-03-15 2019-03-06 Inhibiteur de l'expression du facteur lié à la formation osseuse ou au facteur lié à la calcification dans un tissu extrasquelettique WO2019176693A1 (fr)

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JP2020506438A JPWO2019176693A1 (ja) 2018-03-15 2019-03-06 骨外組織における骨形成関連因子又は石灰化関連因子の発現抑制剤
JP2023133764A JP2023144116A (ja) 2018-03-15 2023-08-21 骨外組織における骨形成関連因子又は石灰化関連因子の発現抑制剤

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JPH0776523A (ja) * 1993-07-21 1995-03-20 Dai Ichi Seiyaku Co Ltd 異所性骨化症予防・治療薬
JP2000159677A (ja) * 1998-12-01 2000-06-13 Seikagaku Kogyo Co Ltd ヒアルロン酸を有効成分とする異所性石灰化抑制剤
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WO2014042265A1 (fr) * 2012-09-14 2014-03-20 出光興産株式会社 Composé polymère, substance pour éléments électroniques, substance pour éléments électroluminescents organiques, et élément électroluminescent organique

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