Application of halofuginone in preparation of medicine for treating ectopic ossification

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of halofuginone in preparation of a medicine for treating ectopic ossification. The invention provides an application of halofuginone in preparation of a medicine for treating ectopic ossification. Through imaging observation, histological section staining result observation and blood vessel fluorescence staining observation, a positive control group has obvious hyperostosis and bone structure formation at the mouse achilles tendon, obvious cartilage formation in a bone formation area and obvious blood vessel formation at the heterotopic ossification mouse achilles tendon, and the positive control group has obvious cartilage formation at the heterotopic ossification mouse achilles tendon and obvious cartilage formation at the heterotopic ossification mouse achilles tendon. However, in a halofuginone administration group, no obvious hyperostosis, no obvious bone formation and no cartilage accumulation are found, and no obvious vascularization is found at the achilles tendon of the ectopic ossification mouse. The halofuginone has good effects of improving bone formation, cartilage accumulation and vascularization, namely the halofuginone has a good effect of resisting heterotopic ossification.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to an application of halofuginone in preparing a medicine for treating heterotopic ossification. Background Art

[0002] Heterotopic ossification is the formation of ectopic lamellar bone in soft tissue. The disability rate of heterotopic ossification is high, and more than 20% of patients have obvious functional impairment due to soft tissue defects, joint contractures and chronic pain. For patients with traumatic brain injury, the heterotopic ossification rate is as high as 50%. Heterotopic ossification is considered a complication after trauma, burns, nervous system injury and major orthopedic surgery, and it is still a challenge in clinical treatment.

[0003] Halofuginone, also known as halofuginone, is a derivative of febrifugine. It is a low molecular weight quinazolinone alkaloid (495Da) isolated from the plant Dichroa febrifuga. Its chemical name is 7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl(acetonyl)]-4(3H)-quinazolinone hydrobromide. Its molecular formula is C 16 H 17 BrClN 3 O 3 The main pharmacological effects of halofuginone include pulmonary vasodilator, anti-fibrosis, and treatment of chronic graft-versus-host disease (cGvHD) of the skin, but there are no reports on the anti-heterotopic ossification effect of halofuginone. Summary of the invention

[0004] The present invention aims to solve one or more technical problems existing in the above-mentioned prior art, and at least provide a beneficial choice or create conditions. Specifically, the present invention provides a use of halofuginone in the preparation of a drug for treating heterotopic ossification, which can effectively reduce abnormal bone formation, cartilage accumulation and blood vessel formation in soft tissues at the site of trauma, and has a good anti-heterotopic ossification effect.

[0005] A first aspect of the present invention provides a use of halofuginone in the preparation of a medicament for treating heterotopic ossification.

[0006] Preferably, the active ingredient of the drug includes halofugone.

[0007] Preferably, the content of halofuginone in the drug is 1.6-2.5 mg / mL; further preferably, the content of halofuginone in the drug is 1.8-2.2 mg / mL; further preferably, the content of halofuginone in the drug is 2 mg / mL.

[0008] Specifically, in the drug, halofuginone can be used as the only active ingredient, or can be combined with other pharmaceutically approved substances.

[0009] Preferably, the medicament further comprises a buffer.

[0010] Preferably, the buffer comprises dimethyl sulfoxide (DMSO), polyethylene glycol (PEG300), polyoxyethylene sorbitan monooleate (Tween-80), and phosphate buffered saline (PBS).

[0011] Preferably, the mass ratio of DMSO, PEG300, Tween-80 and PBS is (1.6-3.0):(7.0-9.0):1:(8.0-10.0); further preferably, the mass ratio of DMSO, PEG300, Tween-80 and PBS is (1.8-2.8):(7.5-8.5):1:(8.5-9.5); further preferably, the mass ratio of DMSO, PEG300, Tween-80 and PBS is 2:8:1:9.

[0012] Preferably, the medicament contains pharmaceutically acceptable excipients.

[0013] Preferably, the drug is prepared in any pharmaceutically acceptable dosage form.

[0014] Preferably, the dosage form includes any one of tablets, capsules, granules, oral liquids, injections, sprays, ointments, creams, gels, and inhalants.

[0015] Preferably, the halofugone has the following structural formula:

[0016]

[0017] A second aspect of the present invention provides a drug for treating heterotopic ossification.

[0018] Specifically, the drug includes the halofuginone described in the first aspect of the present invention.

[0019] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects:

[0020] The present invention provides an application of halofuginone in the preparation of a drug for treating heterotopic ossification. Through imaging observation, histological section staining result observation, and vascular fluorescence staining observation, the positive control group has obvious bone hyperplasia at the Achilles tendon of mice, bone structure formation, obvious cartilage formation in the bone formation area, and obvious blood vessel formation at the Achilles tendon of heterotopic ossification mice, while the halofuginone administration group has no obvious bone hyperplasia, no obvious bone formation and cartilage accumulation, and no obvious blood vessel formation at the Achilles tendon of heterotopic ossification mice. It shows that halofuginone can effectively reduce abnormal bone formation, cartilage accumulation and blood vessel formation in soft tissues at the trauma site, and further shows that halofuginone has a good effect of resisting heterotopic ossification. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The CT scan images of the three groups of experimental mice of the present invention after 10 weeks of drug intervention treatment;

[0022] Figure 2 The bone mass diagram of the Achilles tendon of the three groups of experimental mice treated with drugs for 10 weeks;

[0023] Figure 3 The results of histological staining of Achilles tendons of three groups of experimental mice treated with drugs for 10 weeks;

[0024] Figure 4 The results of immunofluorescence staining of blood vessels in Achilles tendon tissue of three groups of experimental mice treated with drugs for 10 weeks;

[0025] Figure 5 This is a statistical diagram of the ratio of positive blood vessels to total blood vessels in three groups of experimental mice after 10 weeks of drug intervention. DETAILED DESCRIPTION

[0026] In order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the following embodiments are listed for illustration. It should be pointed out that the following embodiments do not limit the protection scope of the present invention.

[0027] Unless otherwise specified, the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0028] Example 1

[0029] Study on the effect of halofuginone on heterotopic ossification

[0030] Control drug: intraperitoneal injection of solvent DMSO.

[0031] Halofuginone solution: 10 mg of halofugone was dissolved in 5 mL of buffer solution (10% DMSO, 40% PEG300, 5% Tween-80 and 45% PBS), and mixed well until clear to prepare a 2 mg / mL halofugone solution.

[0032] Experimental mice: C57BL / J mice were provided by the Animal Experiment Center of Southern Medical University in Guangdong Province and kept in a sterile animal room. The mouse cages and utensils used were strictly disinfected, and they were free to eat and drink purified water. Before the experiment, the mice were observed for clinical symptoms and their activity was checked for 2 consecutive days for use.

[0033] Experimental methods

[0034] Experimental grouping: 70 C57BL / J mice were raised to 3 months of age, weighed one by one, and mice with poor vitality and excessive weight were eliminated. The remaining mice were randomly divided into 3 groups (Group I, Group II, and Group III), with 20 mice in each group, and the total weight of mice in each group was appropriately adjusted to be roughly equal.

[0035] Experimental treatment: Group I was the blank control group (the mice did not undergo Achilles tendon transection model). Except for Group I, the mice in other groups underwent Achilles tendon transection model establishment; Group II was the positive control group, which was intraperitoneally injected with solvent DMSO every other day, with 100 μL per intraperitoneal injection; Group III was the fusinone administration group, which was intraperitoneally injected with fusinone solution every other day, with 100 μL per intraperitoneal injection.

[0036] The groups of experimental mice are shown in Table 1.

[0037] Table 1: Grouping of experimental mice

[0038] Group Number of mice Modeling treatment Drug treatment Group I (blank control group) 20 No modeling No Addition Group II (positive control group) 20 Achilles tendon transection DMSO Group III (halofuginone administration group) 20 Achilles tendon transection Halofuginone solution

[0039] The mental state, food intake, feces, etc. of the mice were observed and recorded every day. All mice were weighed one by one on the 7th day after Achilles tendon transection modeling, and drug intervention was performed 7 days after modeling. The drug intervention treatment lasted for 10 weeks, and then the following experimental analysis was performed.

[0040] 1. Imaging Observation

[0041] After 10 weeks of drug intervention, the mice were killed and the lower limbs of the three groups of experimental mice were collected for CT scanning. The CT scan images are shown in the figure Figure 1 As shown, Figure 1 Figure (a) in the middle is the CT scan image of the blank control group. Figure 1 The middle (b) figure is the CT scan image of the positive control group. Figure 1 The middle (c) figure is a CT scan image of the halofuginose administration group.

[0042] The bone volume (BV) of the Achilles tendon of mice was counted and the formation of heterotopic ossification in the Achilles tendon was observed. Figure 2 As shown. Among them, Figure 2 The control in the middle horizontal axis represents the blank control group, the Achilles tendon transection model represents the positive control group, and the halofuginone represents the halofuginone administration group; the vertical axis BV (%) represents the bone formation volume at the Achilles tendon of mice, **** indicates a significant statistical difference (p<0.0001), and ns indicates no statistical difference.

[0043] Depend on Figure 1 It can be seen that obvious bone hyperplasia was observed in the mice in the positive control group. Compared with the positive control group, no obvious bone hyperplasia was found in the Achilles tendon of the mice in the fufurin-treated group.

[0044] Depend on Figure 2 It can be seen that the bone formation volume BV at the Achilles tendon of mice in the fusinone-treated group was significantly downregulated compared with the positive control group and was basically equivalent to that of the blank control group.

[0045] Depend on Figure 1 and Figure 2 It can be seen that halofuginone can improve bone hyperplasia in the Achilles tendon of mice and reduce the volume of bone formation in the Achilles tendon of mice.

[0046] 2. Observation of histological section staining results

[0047] After 10 weeks of drug intervention, the mice were killed, and the Achilles tendon specimens of the three groups of experimental mice were subjected to histological staining observation, including hematoxylin and eosin staining (H&E staining) and Safranin O and fast green staining. The specific test methods are as follows:

[0048] (1) Sampling: After 10 weeks of drug intervention, the mice were killed and the area below the knee joint to the paw of the three groups of mice was taken and placed in a pre-prepared fixative (10% formalin fixative) to denature and coagulate the proteins of the tissues and cells to prevent autolysis of the cells after death or decomposition by bacteria, thereby maintaining the original morphological structure of the cells and obtaining tissue blocks;

[0049] (2) Dehydration and transparency: Use low to high concentrations of alcohol (70%, 80%, 90%, 95%, and 100% alcohol, respectively) as a dehydrating agent for 1 hour to gradually remove the water in the tissue block. Then dissolve the tissue block in paraffin-based transparent agent xylene for transparency. Use xylene to replace the alcohol in the tissue block to obtain a transparent tissue block.

[0050] (3) Wax embedding: the transparent tissue block obtained in step (2) is placed in the melted paraffin, placed in a wax melting box for heat preservation, and embedded after the paraffin is completely immersed in the tissue block: a paraffin embedding box is used, the melted paraffin is poured in, and the tissue block immersed in the paraffin is quickly clamped and placed in the box, and cooled and solidified into a block;

[0051] (4) Sectioning and pasting: The embedded wax block obtained in step (3) is fixed on a microtome and cut into 5 μm thick sections;

[0052] (5) Dewaxing: Before staining, use xylene to remove the paraffin in the sections, then dehydrate for 20 minutes through high to low concentrations of alcohol (100%, 95%, 90%, 80%, 70%), then put into distilled water and stain;

[0053] (6) Staining: H&E and Safranin O and fast green staining are commonly used to increase the color difference of different parts of the tissue cell structure and facilitate observation;

[0054] Principle of H&E staining: Hematoxylin (H) is a basic dye that can stain the cell nucleus and ribosomes in the cell into blue-purple. The structures stained by basic dyes are basophilic. Eosin (Eosin, E) is an acidic dye that can stain the cytoplasm into red or light red. The structures stained by acidic dyes are eosinophilic.

[0055] Safranin O and fast green staining principle: basophilic cartilage combines with the basic dye Safranin O to show red, and eosinophilic bone combines with the acidic dye fast green to show green or blue, which contrasts sharply with the red cartilage, thereby distinguishing cartilage tissue from bone tissue;

[0056] The process of H&E staining is as follows:

[0057] ① Place the slices that have been immersed in distilled water into a hematoxylin aqueous solution for staining for 5 minutes;

[0058] ②Separate in hydrochloric acid and ethanol for 20 seconds;

[0059] ③ Rinse with running water for 1 hour and then put into distilled water for 10 seconds;

[0060] ④ Dehydrate in 70% and 90% alcohol for 10 minutes each;

[0061] ⑤ Place in alcohol eosin staining solution for 3 minutes;

[0062] The process of Safranin O and fast green staining is:

[0063] ① Place the slices that have been soaked in distilled water into a hematoxylin aqueous solution and stain with hydrochloric acid for 5 minutes;

[0064] ②Separation in hydrochloric acid and ethanol, 20 seconds;

[0065] ③ Rinse with running water for 1 hour and then put into distilled water for 10 seconds;

[0066] ④ After staining with fast green dye for 5 minutes, quickly wash the sections with acetic acid solution for 10-15 seconds to remove the remaining fast green and dry them;

[0067] ⑤ Transfer to safranin dye and dye for 20 minutes, and use 90% and 100% alcohol to rinse off excess safranin dye;

[0068] (7) Dehydration and transparency: The stained sections are dehydrated with pure alcohol and then transparentized with xylene to obtain transparent sections;

[0069] (8) Sealing: Add Canada balsam to the transparent slice obtained in step (7), cover with a cover glass for sealing, wait for the balsam to dry slightly, and affix a label to obtain a slice specimen;

[0070] (9) Observation: Observe and analyze the H&E-stained, Safranin O-stained and fast green-stained section specimens under a microscope.

[0071] The results of histological staining of Achilles tendons of the three groups of experimental mice are as follows Figure 3 As shown. Among them, Figure 3 Figures (a) and (d) are the results of H&E staining and safranin green staining of the blank control group, respectively; Figure 3 Figures (b) and (e) are the results of H&E staining and safranin green staining of the positive control group, respectively; Figure 3 Figures (c) and (f) show the results of H&E staining and safranin green staining in the fusinone-treated group, respectively.

[0072] Depend on Figure 3 It can be seen that for the positive control group, H&E staining can observe the formation of bone structure with obvious boundaries with the surrounding Achilles tendons and a large amount of bone-like tissue inside the Achilles tendon of mice, Safranin O and fast green staining can observe chondrocytes in the bone formation area that are combined with basophilic dyes and appear red, indicating obvious cartilage formation, while no obvious bone structure formation and cartilage accumulation were observed in the halofuginose-treated group, indicating that halofuginose has a good effect on improving bone formation and cartilage accumulation.

[0073] 3. Vascular fluorescence staining results

[0074] The Achilles tendon specimens of the three groups of experimental mice were subjected to vascular immunofluorescence staining. H-type blood vessels are specifically present in bone tissue. This type of blood vessel is mainly distinguished from other blood vessel types by immunofluorescence co-staining of specific cell surface markers (platelet endothelial cell adhesion molecule (CD31) and endothelial cell membrane-bound mucin (Endomucin)). The specific method is as follows:

[0075] (1) Systemic perfusion: In order to avoid interference of intravascular platelets or red blood cells with fluorescent staining, the mice should be perfused before knee joint specimen collection.

[0076] a: After 10 weeks of drug treatment, the three groups of mice were intraperitoneally injected with 300-400 μL of anesthetic. After anesthesia, the mice were fixed on a foam board in a supine position with their limbs spread out, and the foam board was placed on a washbasin at an angle of 45° to the ground.

[0077] b: Separate the mouse skin along the xiphoid process to both sides to expose the abdominal wall. After the abdominal wall is exposed, open the abdominal cavity along the lower edge of the ribs to expose the liver and diaphragm to the visual field; open the diaphragm to expose the heart and lungs, and use microscissors to cut an opening in the right atrial appendage to facilitate the perfusion fluid to flow out from the right atrial appendage after passing through the entire systemic circulation, fully flushing the blood cells in the experimental animal;

[0078] c: Use a scalp vein needle to pierce the heart along the apex, and use 20mL of PBS buffer solution containing heparin to flush out the blood in the systemic circulation. When the liver changes from dark red to brown, replace the perfusion solution, and use 4% paraformaldehyde to perfuse and fix the blood vessels in the body. During the paraformaldehyde perfusion, it can be seen that the muscles of the mouse body spasm, and the mouse tail is stiff and tilted upward due to spasm, indicating that the 4% paraformaldehyde has flowed through the entire systemic circulation of the mouse. At this time, the perfusion is completed and the next step of sampling is carried out;

[0079] (2) Sampling and decalcification: The lower femur, knee joint and upper tibia of the knee joint specimen were obtained; at the same time, the ex vivo specimen was placed in 4% paraformaldehyde for fixation for 24 hours, and then replaced with 10% ethylenediaminetetraacetic acid (EDTA) rapid decalcification solution after 24 hours. The specimen was decalcified on a shaker at 4°C for 14 days until the syringe needle could easily pierce the bone cortex, and the decalcification was completed to obtain the decalcified bone tissue specimen;

[0080] (3) Dehydration and embedding: Before ethanol dehydration, the decalcified bone tissue specimen obtained in step (2) is placed in an embedding box and rinsed under running water for 30 minutes to fully wash the decalcification liquid on the surface of the specimen; then, it is immersed in a gradient ethanol dehydration solution for dehydration: I 70% ethanol for 1 hour → II 70% ethanol for 1 hour → 80% ethanol for 1 hour → I 95% ethanol for 1 hour → II 95% ethanol for 1 hour → I anhydrous ethanol for 1 hour → II anhydrous ethanol for 1 hour → III anhydrous ethanol for 1 hour → I xylene for 30 minutes → II xylene for 30 minutes → I wax cylinder for 1 hour → II wax cylinder for 2 hours → tissue embedding; after embedding, the wax block is placed at -20°C overnight to fully condense the wax block, and sliced ​​every other day, with the thickness of the paraffin section being 0.4 μm;

[0081] (4) Immunofluorescence staining:

[0082] a: Take the paraffin section specimen obtained in step (3) and dewax and rehydrate: I xylene 15 min → II xylene 15 min → I anhydrous ethanol 5 min → II anhydrous ethanol 5 min → I 95% ethanol 5 min → II 95% ethanol 5 min → 80% ethanol 5 min → 70% ethanol 5 min → distilled water 5 min → PBS 2 min;

[0083] b: Antigen repair: For subchondral bone vascular endothelial marker protein antigen repair, we use pH = 9.0 EDTA antigen repair solution for repair. Pour the repair solution into a glass trough and place it in a constant temperature water bath to heat to 70 degrees Celsius. Then put the specimen slices into the repair solution for repair for 30 minutes. After the repair is completed, take the glass trough out of the water bath and place it at room temperature until the temperature of the repair solution and the glass slide returns to room temperature. Wash twice with phosphate-buffered saline (PBST) and three times with phosphate buffered saline (PBS), each time for 5 minutes.

[0084] c: Blocking: wipe the water stains on the slide, circle the specimen with an immunohistochemistry pen, and use 15% goat serum for blocking. Drop 50 μL of blocking solution on each specimen, immerse the entire specimen in the blocking solution, and block at room temperature for 1 hour;

[0085] d: Antibody incubation: Use 15% goat serum blocking solution as the antibody diluent, add two primary antibodies to the blocking solution according to their respective dilution ratios (CD31 (1:200), Endomucin (1:50)). To avoid cross-reaction, different species of primary antibodies are used, CD31 is a rabbit polyclonal antibody, and Endomucin is a rat monoclonal antibody. After absorbing the blocking solution on the specimen, add the antibody dropwise to the specimen to immerse the entire specimen, and incubate the primary antibody in a 4-degree Celsius cold storage overnight; on the second day, take the specimen box back from the 4-degree Celsius cold storage to the staining room to restore to room temperature. The primary antibody can be reused 2-3 times, and the slide is placed in room temperature PBS buffer and washed 3 times, 5 minutes each time;

[0086] e: Incubate the secondary antibody: Use 15% goat serum blocking solution as the antibody diluent, add the two secondary antibodies into the blocking solution according to their respective proportions. The preparation of the secondary antibody should be done in a dark room away from light to avoid quenching of the fluorescent secondary antibody. Prepare the corresponding fluorescent secondary antibody. The secondary antibody selected for CD31 is goat anti-rabbit 549 fluorescent antibody, and the secondary antibody selected for Endomucin is goat anti-rat FITC fluorescent antibody. Incubate for 1 hour away from light.

[0087] f: After the secondary antibody incubation, wash three times with PBS buffer in a dark room, 5 minutes each time; wipe dry the liquid around the specimen, seal the slide with anti-fading 4',6-diamidino-2-phenylindole (DAPI) mounting medium, and seal the edge of the coverslip with nail polish to prevent the coverslip from sliding. h: Observe under an Olympus confocal microscope, collect photos, and quantitatively count the positive cells.

[0088] The immunofluorescence staining photos of blood vessels in the three groups of experimental mice are shown in Figure 4 As shown. Among them, Figure 4 Middle (a) is a photo of blood vessel immunofluorescence staining of mice in the blank control group; Figure 4 Middle (b) is a photo of blood vessel immunofluorescence staining of mice in the positive control group; Figure 4The middle (c) figure shows the immunofluorescence staining of blood vessels in mice in the fusinone-treated group.

[0089] The statistical diagram of the ratio of positive blood vessels to total blood vessels in the three groups of experimental mice is shown in Figure 5 As shown, the vertical axis HV / VV (%) represents the ratio of positive blood vessels to total blood vessels, **** represents a significant statistical difference (p<0.0001), and ns represents no statistical difference.

[0090] Depend on Figure 4 The results of fluorescence staining showed that for the positive control group, obvious yellow fluorescence was produced in the Achilles tendons of heterotopic ossification mice, indicating that blood vessels were formed, while for the group treated with fusinone, no obvious blood vessel formation was observed in the Achilles tendons of heterotopic ossification mice.

[0091] Depend on Figure 5 It can be seen that after the use of halofuginone, the number of H-type blood vessels was significantly reduced compared with the positive control group, indicating that halofuginone has the effect of inhibiting angiogenesis, that is, it has a good effect of resisting heterotopic ossification.

[0092] Through imaging observation, histological section staining observation, and vascular fluorescence staining observation, the positive control group had obvious bone hyperplasia in the Achilles tendon of mice, bone structure formation, obvious cartilage formation in the bone formation area, and obvious blood vessel formation in the Achilles tendon of mice with heterotopic ossification, while the halofuginone-administered group had no obvious bone hyperplasia, no obvious bone formation and cartilage accumulation, and no obvious blood vessel formation in the Achilles tendon of mice with heterotopic ossification. This shows that halofuginone has a good effect of improving bone formation, cartilage accumulation and blood vessel formation, that is, it shows that halofuginone has a good effect of resisting heterotopic ossification.

[0093] The above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. Application of halofuginone in the preparation of drugs for the treatment of heterotopic ossification.

2. The use according to claim 1, characterized in that: The active ingredient of the drug includes halofuginone.

3. The use according to claim 2, characterized in that: In the medicine, the content of halofuginone is 1.6-2.5 mg / mL.

4. The use according to claim 1, characterized in that: The medicament also includes a buffer.

5. The use according to claim 4, characterized in that: The buffer includes dimethyl sulfoxide, polyethylene glycol, polyoxyethylene sorbitan monooleate and phosphate buffer.

6. The use according to claim 5, characterized in that: The mass ratio of dimethyl sulfoxide, polyethylene glycol, polyoxyethylene sorbitan monooleate and phosphate buffer is (1.6-3.0):(7.0-9.0):1:(8.0-10.0).

7. The use according to claim 1, characterized in that: The drug contains pharmaceutically acceptable excipients.

8. The use according to claim 1, characterized in that: The drug is prepared into any pharmaceutically acceptable dosage form.

9. The use according to claim 8, characterized in that: The dosage form includes any one of tablets, capsules, granules, oral liquids, injections, sprays, ointments, creams, gels, and inhalants.

10. A drug for treating heterotopic ossification, characterized in that: The drugs include halofuginone.

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