WO2019176693A1 - Inhibitor of expression of bone formation-related factor or calcification-related factor in extraskeletal tissue - Google Patents

Abstract

Provided is an inhibitor of the expression of a bone formation-related factor or a calcification-related factor in an extraskeletal tissue. An inhibitor of the expression of a bone formation-related factor in an extraskeletal tissue, the inhibitor being characterized by comprising phytic acid. The bone formation-related factor is any one of ALPL, RUNX2, BGLAP and the like. An inhibitor of the expression of a calcification-related factor in an extraskeletal tissue, the inhibitor being characterized by comprising phytic acid. The calcification-related factor is any one of SLC20A1, SLC20A2, ENPP1, ALPL, SPP1 and the like. These inhibitors can prevent heterotopic ossification and ectopic calcification, respectively, when administered intravenously.

Description

Expression inhibitor of osteogenesis-related factor or calcification-related factor in extra-bone tissue

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. In cultured osteoblast cell lines, 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.

In addition, there are transcription factors such as RUNX2, SPP1, MSX2, DLX5, TWIST1, and JUN as markers for osteoblasts. 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.

However, when the above-mentioned bone formation-related factors are expressed in extra-osseous tissue, 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. There is a case. In addition, 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. For example, the joint region is accompanied by a limited range of motion, which significantly reduces the quality of life (QOL). In blood vessels, it is related to cardiovascular events and life prognosis.

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.

No. 2006/129882

However, the substances described in 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.

According to the present invention, it is possible to appropriately suppress the expression of a bone formation-related factor or a calcification-related factor in extra-osseous tissue.

It is a figure which shows the effect of phytic acid administration in an ectopic ossification model, (A) is ectopic ossification in which ossification tissue is seen in the transplant part of the atelocollagen which impregnated BMP-2 to the mouse muscle tissue It is a micro CT image of a model, and (B) shows that the amount of ossified tissue decreases depending on the dose of phytic acid. 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. It is a photograph of Kossa staining showing the effect of phytic acid administration in a calcification model of a mouse aortic organ under 2.6 μmM phosphoric acid (Pi) loading environment. It is a photograph of immunostaining of the osteoblast marker ALPL when phytic acid is administered to a calcification model of a mouse aortic organ under an environment loaded with 2.6 mM phosphate (Pi). It is a figure showing the state of gene expression when phytic acid was administered to a calcification model of mouse aortic organ under 2.6 M mM phosphate (Pi) load environment, of which (A) is Alpl, (B) is Runx2, (C) is Bglap, and (D) is Slc20a1. 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 | concentration at the time of administering a phytic acid intravenously to a mouse | mouth. It is a figure which shows the serum inorganic phosphate density | concentration at the time of administering a phytic acid intravenously to a mouse | mouth. It is a photograph of the arterial arch of Enpp1 mutant mouse, of which (A) is vehicle administration, (B) is 0.4 mg / body / day sodium phytate administration, (C) is 0.04 mg / body / day sodium phytate Administration. It is a figure which shows the bone morphometry result of the tibia proximal end about Enpp1 mutant mouse, (A) is cortical bone mass, (B) is sea surface bone mass, (C) is cortical bone density (D) Is the sea surface bone density. It is a figure which shows the result of the serum sample which administered sodium phytate and vehicle of 0.4 mg / body / day *, (A) is a serum zinc density | concentration, (B) is a serum iron density | concentration.

Hereinafter, embodiments of the present invention will be specifically described with reference to the accompanying drawings. However, the embodiments are for facilitating understanding of the principle of the present invention, and the scope of the present invention is as follows. The present invention is not limited to the embodiments, and other embodiments in which those skilled in the art appropriately replace the configurations of the following embodiments are also included in the scope of the present invention.

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. In addition to being approved as a food additive as a sour agent and a pH adjuster, various physiological functions including an antioxidant action can be expected, and many uses as functional ingredients are also disclosed.

However, it has not been known that 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 according to the present invention contains phytic acid as a pharmaceutically effective amount. For example, tablets, granules, fine granules, capsules It is possible to make preparations for oral administration such as agents, various liquid preparations suitable for oral administration, or preparations for parenteral administration such as injections and suppositories.

Among the preparations for parenteral administration, 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 . Examples of the aqueous medium include water or a medium containing water. As water, sterilized water is used. Examples of the medium containing water include physiological saline, PBS (phosphate buffered physiological saline), lactic acid-containing Ringer's solution, and the like.

In the preparation for injection, the content of phytic acid or a salt thereof is not particularly limited, but is, for example, 1 μg / mL to 10 μg / mL, preferably 100 μg / mL to 1 μm mg / mL.

In the preparation for injection, additives usually used in the art can be appropriately used. Examples of the additive include isotonic agents, stabilizers, buffers, preservatives, chelating agents, antioxidants, and solubilizing agents. Examples of the isotonic agent include sugars such as glucose, sorbitol and mannitol, sodium chloride, glycerin, propylene glycol, polyethylene glycol and the like. Examples of the stabilizer include sodium sulfite. Examples of 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. Specifically, examples of the acids include ascorbic acid, hydrochloric acid, gluconic acid, acetic acid, lactic acid, boric acid, phosphoric acid, sulfuric acid, tartaric acid, and citric acid. Examples of 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.

In the present invention, 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.

In this regard, there is a view that ectopic ossification is suppressed by the chelating action of phytic acid, but the present inventors have an important mechanism of suppression of ectopic ossification by phytic acid in chelating action. Instead, it was found to be the suppression of the expression of bone formation-related factors or mineralization-related factors.

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.

In this specification, “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. On the other hand, “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.

(1) 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. As shown in the vehicle of FIG. 1 (A), the ossified tissue of the ectopic ossification model was confirmed in the micro CT image.

Using 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. As shown in FIGS. 1 (A) and (B), the amount of ossified tissue decreased depending on the dose of phytic acid. In FIG. 1B, the vertical axis represents the bone mass (mm ³ ) obtained by micro CT.

(2) Example 2 Effect of phytic acid administration on calcification of mouse aortic organ culture during phosphate loading The thoracic aorta was removed from 4-week-old C57BL / 6 male mice and cut into lengths of 2 to 5 mm (FIG. 2). (A)). This was placed on a culture dish and cultured at 37 ° C. for 10 days with DMEM (High glucose) containing 15% fetal calf serum. For phosphate loading environment, 2.6 mM phosphoric acid (Pi) was added to the culture.

After 10 days of culture, calcified tissue was observed in the mouse aorta. Matrix mineralization, including bone matrix, is initiated by matrix vesicles produced and secreted by osteoblasts present on the bone surface (matrix vesicular calcification) and formed inside the matrix vesicles 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. Thus, osteoblasts are cells responsible for bone formation and induce calcification.

In this mouse aorta organ culture model at the time of phosphate loading, 1 μM, 3 μM or 10 μM phytic acid was added to the culture medium, and the presence or absence of calcified tissue was observed after 10 days of culture. As shown in FIGS. 2 (B) and 2 (C), in the micro CT image, the amount of calcified tissue decreased depending on the dose of phytic acid. In FIG. 2 (C), the vertical axis represents the amount of calcified tissue (mm ³ ).

(3) Example 3 Calcified tissue staining diagram of mouse aortic organ culture at phosphate loading For the mouse aortic organ culture model under phosphate loading environment in Example 2 above, 4% paraformaldehyde PBS was used after completion of the culture. A paraffin specimen was prepared by fixing. 5 μm 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.

As shown in FIG. 3, it is understood that the portion of phytic acid stained black in a dose-dependent manner is reduced, and the amount of calcified tissue is reduced. In FIG. 3, the scale bar is 25 μm.

(4) 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) is a glycoprotein present in the cell membrane. ALP that exists specifically in bone tissue is called BAP, is present in the cell membrane, and binds to the membrane via phosphatidylinositol. During the period when osteoblast function is enhanced and bone formation activity is enhanced, blood BAP is elevated, so ALP is an osteoblast 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. As shown in 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. In FIG. 4, the scale bar is 75 μm.

(5) 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. Here, 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.

As shown in FIGS. 5 (A), (B) and (C), it was shown that the expression of osteogenesis-related factors was suppressed in the presence of phytic acid. Further, as shown in FIG. 5 (D), it was shown that the expression of calcification-related factors was suppressed in the presence of phytic acid.

(6) 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. In this example, the inhibitory effect of phytic acid on arterial calcification of warfarin was verified.

When the newborn SD rat was 15 days old, 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. At 20 days of age, oral administration of vitamin K1 (1.5 mg / 100 g body weight / day) was started. At the age of 21 days, sodium phytate (0.4 and 2 mg / 50-120 g body weight / day) was continuously administered from the right jugular vein using an osmotic pump. After wearing the osmotic pump, weaning, oral administration of vitamin K1 and continuous high-phosphate diet were continued, and warfarin (15 mg / 100 g body weight) was subcutaneously administered every 12 hours from the next 22 days of age. On the 12th day from the start of warfarin administration, the artery (from the aortic arch to the femoral artery) was removed and fixed with 4% paraformaldehyde PBS, and stained with alizarin red S, which stains the calcified tissue red. As a result, no calcification was observed in the group that did not receive warfarin as shown in FIG. 6 (A), but when warfarin was administered as shown in FIG. Was observed. On the other hand, even when warfarin was administered, calcification of the aorta was sufficiently suppressed when phytic acid was further administered.

(7) 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 ™ 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.

(8) 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. At 4 weeks after birth, 0.004 mg / body / day, 0.04 mg / body / day, 0.4 mg / body / day sodium phytate was continuously administered from the right jugular vein using an osmotic pump (Alzet), and 6 weeks after birth Confirmed arterial vascular calcification. In this mouse, calcification can be confirmed in a scattered manner centering on the bifurcation of the femoral artery from the arterial arch and the lower aorta. FIG. 9 shows an arterial arch. Of these, (A) is Vehicle, (B) is 0.4 mg / body / day, and (C) is 0.04 mg / body / day. As shown in FIG. 9, phytic acid almost completely suppressed vascular calcification stained with alizarin red at a concentration of 0.04 mg / body / day or more.

(9) 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.

(10) Example 10 Serum Iron Ion and Zinc Ion Concentration at Effective Phytic Acid Concentration The following serum samples were analyzed to confirm the effect of phytic acid on iron and zinc concentrations in serum.

a) Serum sample obtained from the mouse of Example 7 (continuous intravenous administration for 1 week)
b) Serum sample administered with 0.4 mg / body / day sodium phytate and vehicle in Example 8 (continuous intravenous administration for 2 weeks) c) Untreated mouse serum reared on normal diet simultaneously with Example 8 sample

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. When the above samples were compared, there was no effect of phytic acid on serum zinc and iron concentrations.

From the results of this Example, 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.

It can be used to suppress ectopic ossification or ectopic calcification.

Claims (6)

1. An agent for suppressing the expression of an osteogenesis-related factor in extraskeletal tissue, comprising phytic acid.
2. The bone formation-related factor is any one of osteoblast differentiation-related factors such as ALPL, RUNX2, or BGLAP. Agent.
3. An inhibitor of the expression of calcification-related factors in extraskeletal tissues, characterized by containing phytic acid.
4. The expression of a calcification-related factor in extraskeletal tissue according to claim 3, wherein the calcification-related factor is one of bone calcification-related factors such as SLC20A1, SLC20A2, ENPP1, ALPL, and SPP1. Inhibitor.
5. An agent for the prevention and / or treatment of ectopic ossification or ectopic calcification resulting from the expression of an osteogenesis-related factor or calcification-related factor, comprising phytic acid.
6. The ectopic calcification is vascular calcification associated with renal disease or dialysis, vascular calcification due to arteriosclerosis, or calcification in infant systemic arterial calcification, and the ectopic ossification is progressive. The ectopic ossification or ectopic calcification according to claim 5, which is ossification in ossification fibrodysplasia, posterior longitudinal ligament ossification, or yellow ligament ossification Prophylactic and / or therapeutic agent.

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