Use of matrix metalloproteinase inhibitor in preparation of drug for preventing or treating osteoarthritis cartilage injury

Abstract

The present invention relates to the field of geriatric treatment, in particular to the use of a matrix metalloproteinase inhibitor MSAB or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating osteoarthritis cartilage injury. In the present invention, MSAB is used to inhibit the expression of matrix metalloproteinase in chondrocytes, so that the damage to articular cartilage structures is reduced, and the effect of preventing or treating osteoarthritis is achieved.

Description

Application of matrix metalloproteinase inhibitors in the preparation of drugs for preventing or treating osteoarthritis cartilage damage Technical Field

[0001] The present invention relates to the field of treatment of geriatric diseases, and in particular to the use of a matrix metalloproteinase inhibitor in the preparation of a drug for preventing or treating osteoarthritis cartilage damage. Background Art

[0002] Osteoarthritis is a chronic degenerative disease caused by the progressive destruction of articular cartilage and subchondral bone. Its pathological features include cartilage destruction, limited mobility, osteophyte formation, and chronic pain. Currently, the primary treatment for osteoarthritis is total joint replacement surgery, but this approach has several drawbacks: high surgical risks such as infection, bleeding, and thrombosis; potential postoperative complications such as prosthesis loosening and dislocation; limited prosthesis lifespan, which may necessitate further surgical replacement; and the high cost of treatment, which requires extensive medical equipment and personnel, placing a significant financial burden on patients.

[0003] Therefore, there is an urgent need to develop a drug that can effectively cure osteoarthritis. While drug development is based on the understanding and exploration of the molecular mechanisms of the disease, people still know very little about the occurrence and development of osteoarthritis, which has led to the lack of effective drugs for the treatment of osteoarthritis. Technical issues

[0004] The surgery has high risks, such as infection, bleeding, and thrombosis; complications such as prosthesis loosening and dislocation may occur after the operation; the prosthesis has a limited lifespan, and another surgery may be needed to replace the prosthesis; the treatment requires a large amount of medical equipment and medical staff, the cost is high, and it will place a heavy financial burden on the patient. Technical Solutions

[0005] The purpose of the present invention is to overcome the shortcomings of the prior art and solve at least one defect in the above-mentioned background technology.

[0006] To achieve the above objectives, the present invention provides the following technical solutions:

[0007] The present invention provides an application of a matrix metalloproteinase inhibitor in preparing a drug for preventing or treating osteoarthritis cartilage damage. The matrix metalloproteinase inhibitor is methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the matrix metalloproteinase inhibitor achieves the prevention or treatment of osteoarthritis cartilage damage by inhibiting the expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4 and / or Adamts5.

[0009] In some embodiments, the matrix metalloproteinase inhibitor inhibits the expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4 and / or Adamts5 by inhibiting the activation of the WNT / β-catenin signaling pathway.

[0010] In some embodiments, the matrix metalloproteinase inhibitor prevents or treats osteoarthritis cartilage damage by inhibiting meniscus calcification and / or synovial tissue regeneration.

[0011] In some embodiments, the effective concentration of the matrix metalloproteinase inhibitor is 15 mg / kg body weight. Beneficial effects

[0012] Methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate is being investigated as a potential small molecule drug for the treatment of cartilage damage in osteoarthritis. By inhibiting the expression of matrix metalloproteinases (Mmp3, Mmp13, Adamts4, and Adamts5), it effectively suppresses cartilage structural damage during osteoarthritis, providing important insights for the treatment of osteoarthritis. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 is the chemical structural formula of methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate;

[0014] FIG2 shows the qPCR detection results of downstream genes of the β-catenin signaling pathway in ATDC-5 cells in an embodiment, wherein FIG2A and FIG2B respectively represent the mRNA expression levels of Axin2 and Dkk1;

[0015] FIG3 shows the qPCR detection results of extracellular matrix-related molecules in ATDC-5 cells in an embodiment, wherein FIG3A to FIG3D respectively represent the mRNA transcription levels of matrix metalloproteinase genes Mmp3, Mmp13, Adamts4, and Adamts5;

[0016] FIG4 is a flowchart of osteoarthritis mouse modeling and treatment in one embodiment;

[0017] FIG5 is a 3D reconstructed image of a mouse knee joint by Micro-CT in one embodiment;

[0018] FIG6 is a statistical diagram of the volume of osteophytes in the knee joint of mice according to an embodiment;

[0019] FIG7 is a Safranin O-Fast Green staining image of a mouse knee joint in one embodiment;

[0020] FIG8 is a graph showing the degenerative changes in the mouse knee joint according to an embodiment, wherein FIG8A-8E respectively represent the OARSI score, cartilage area, synovitis score, osteophyte size, and osteophyte maturity. Modes for Carrying Out the Invention

[0021] The technical solution of this patent will be further described in detail below in conjunction with specific embodiments. It should be noted that the following detailed description is exemplary and is intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this application belongs.

[0022] Previous studies have shown that multiple signaling pathways, such as Indian hedgehog and TGF-β, can participate in the pathological process of osteoarthritis by directly or indirectly affecting cartilage anabolism and catabolism. Among them, the Wnt / β-catenin signaling pathway, a key cellular signaling pathway, has been shown to be a significant susceptibility factor for osteoarthritis. Studies have shown that abnormal activation of the Wnt / β-catenin signaling pathway in chondrocytes leads to decreased articular cartilage thickness, degradation of the cartilage matrix, and chondrocyte hypertrophy and apoptosis. Furthermore, abnormal activation of the Wnt / β-catenin signaling pathway is also a key pathological phenotype in the knee, hip, mandibular joints, and intervertebral disc joints.

[0023] Research on the molecular mechanisms of the Wnt / β-catenin signaling pathway has revealed that key components of the pathway include Wnt proteins, β-catenin, Frizzled receptors, and LDL receptor-associated proteins. Normally, the Wnt pathway is inactive, and β-catenin is phosphorylated and degraded. When Wnt proteins bind to Frizzled receptors and LDL receptor-associated proteins, Axin and GSK-3β are activated, inhibiting β-catenin degradation, leading to cytoplasmic accumulation and nuclear translocation of β-catenin. Within the nucleus, β-catenin binds to TCF / LEF to form a complex, activating the expression of downstream genes in the Wnt / β-catenin signaling pathway. Mouse and human osteoarthritis models have demonstrated significant upregulation of WISP-1 protein in articular cartilage and synovial tissue, as well as upregulation of matrix metalloproteinases (MMPs) and aggrecanase in chondrocytes and macrophages, all of which promote articular cartilage damage.

[0024] The following examples describe methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate (MSAB), whose structural formula is shown in Figure 1, as a potential small molecule drug for the treatment of osteoarthritis cartilage damage. Currently, MSAB, as an anti-tumor drug in research, has demonstrated growth inhibition against Wnt-dependent cancer cells. This mechanism involves MSAB binding to β-catenin, a key protein in the Wnt / β-catenin signaling pathway. This binding promotes the ubiquitination and degradation of β-catenin, reducing its stability and activity, thereby inhibiting the activity of the Wnt / β-catenin signaling pathway.

[0025] In addition, the following examples used ATDC5 cells as an in vitro experimental cell line for osteoarthritis treatment studies. ATDC5 cells are a mouse fibroblast cell line commonly used in skeletal development research. Derived from mouse embryonic skeletal muscle tissue, they can divide multiple times in vitro and differentiate into chondrocytes and osteocytes. The differentiation pathway of ATDC5 cells is similar to the process of cartilage and bone formation during embryonic development, and therefore they are widely used in the study of skeletal development, cartilage, and bone diseases.

[0026] In the following examples, tumor necrosis factor-α (TNF-α) was used to induce activation of the β-catenin signaling pathway and expression of matrix metalloproteinase-related genes in ATDC5 cells in vitro to investigate the mechanism by which MSAB affects osteoarthritis. TNF-α is an inflammatory mediator that plays a crucial role in the development and progression of osteoarthritis. TNF-α is present in large quantities in the joints of osteoarthritis patients. This TNF-α stimulates synovial cells and chondrocytes to secrete a series of inflammatory factors and enzymes, such as IL-1β, IL-6, and MMPs, further exacerbating arthritis. TNF-α also promotes the infiltration and activation of inflammatory cells, leading to the destruction of articular cartilage and bone resorption, thereby accelerating the progression of osteoarthritis. Therefore, TNF-α has become an important tool for in vitro osteoarthritis research.

[0027] Sources of the biological materials of the present invention: chondrocyte cell line ATDC-5 was purchased from American type culture collection; DMEM culture medium, fetal bovine serum, penicillin, streptomycin, and trypsin were purchased from Gibico; MSAB and TNF-α were purchased from Selleckchem; NGF antibody was purchased from Shanghai Beyotime Biotechnology Co., Ltd.; CGRP antibody was purchased from Abcam; primers used for qPCR were purchased from Sangon Biotech (Shanghai) Co., Ltd.; LABORAS platform was purchased from Metris; and C57BL / 6 mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0028] It should be understood that all statistical comparisons in the following examples were performed using Prism GraphPad statistical software. In addition, all data were compared among different groups using one-way analysis of variance and Tukey's multiple comparison test. Differences were considered statistically significant when P < 0.05, and the results are expressed as mean ± SD.

[0029] The present invention provides a use of a matrix metalloproteinase inhibitor in the preparation of a drug for preventing or treating cartilage damage in osteoarthritis. The invention uses MSAB to reduce osteophyte proliferation and histopathological scores in osteoarthritis mice, alleviates cartilage structural damage, and thus provides a reference for the treatment and prevention of osteoarthritis. The mechanism is related to MSAB inhibiting the activation of the β-catenin signaling pathway and the expression of matrix metalloproteinase-related genes.

[0030] The present invention will be further described below through specific experimental examples.

[0031] Example 1: Effects of MSAB on downstream genes of the β-catenin signaling pathway in chondrocytes

[0032] (1) ATDC5 cells in good growth condition were plated in 12-well culture plates and cultured until the cell density reached 70-80%. They were then divided into four groups: blank treatment group, MSAB treatment group, TNF-α treatment group, and TNF-α + MSAB treatment group, with 3 replicates in each group.

[0033] According to the grouping requirements, the blank treatment group was injected with phosphate buffered saline (PBS), the MSAB treatment group was treated with 50 μmol / L MSAB for 3 h, the TNF-α treatment group was replaced with complete culture medium containing 20 ng / mL TNF-α for 9 h, and the TNF-α+MSAB treatment group was first replaced with complete culture medium containing 20 ng / mL TNF-α for 9 h, and then treated with 50 μmol / L MSAB for 3 h.

[0034] (2) Total RNA was extracted from the four groups of cells obtained in step (1), and real-time quantitative polymerase chain reaction (RT-qPCR) experiments were performed on the downstream genes Axin2 and Dkk1 of the β-catenin signaling pathway in chondrocytes according to the kit instructions.

[0035] Results: Figure 2 shows the qPCR detection results of downstream genes of the β-catenin signaling pathway in ATDC-5 cells, where Figures 2A and 2B represent the mRNA expression levels of Axin2 and Dkk1, respectively. The ordinate represents the gene upregulation fold with β-Actin as the control gene, and the abscissa represents the groups, which are blank treatment group, MSAB treatment group, TNF-α treatment group, and TNF-α+MSAB treatment group, respectively. The Axin2 or Dkk1 expression level of the blank treatment group was set as 1.

[0036] It can be seen that compared with the blank treatment group, the mRNA expression levels of Axin2 and Dkk1 in the TNF-α treatment group were significantly increased, indicating that as a positive control, injection of TNF-α into the chondrocyte cell line ATDC5 can induce the upregulation of mRNA expression of Axin2 and Dkk1, the target genes of the β-catenin signaling pathway.

[0037] Compared with the blank treatment group, the mRNA expressions of Axin2 and Dkk1 in the MSAB treatment group were significantly decreased, indicating that under physiological conditions, MSAB can inhibit the expression of Axin2 and Dkk1, the downstream genes of the β-catenin signaling pathway.

[0038] Compared with the TNF-α-treated group, the TNF-α+MSAB-treated group was injected with 50 μmol / L MSAB after treating cells with TNF-α. At this time, the mRNA expression levels of Axin2 and Dkk1 decreased significantly, indicating that MSAB can inhibit the upregulation of TNF-α-induced expression of genes Axin2 and Dkk1, thereby inhibiting the activity of the β-catenin signaling pathway in ATDC-5 cells and alleviating the progression of osteoarthritis.

[0039] Example 2: Effect of MSAB on the extracellular matrix of chondrocytes

[0040] Total RNA was extracted from the four groups of cells obtained in step (1) of Example 1, and RT-qPCR experiments were performed on the metalloproteinase genes Mmp3, Mmp13, Adamts4, and Adamts5 in chondrocytes according to the kit instructions.

[0041] Results: Figure 3 shows the qPCR detection results of extracellular matrix-related molecules in ATDC-5 cells, where Figures 3A to 3D respectively represent the mRNA transcription levels of metal matrix proteinase genes Mmp3, Mmp13, Adamts4, and Adamts5. The ordinate represents the gene upregulation fold with β-Actin as the control gene, and the abscissa represents the groups, which are blank treatment group, MSAB treatment group, TNF-α treatment group, and TNF-α+MSAB treatment group, respectively. β-Actin was used as the internal control in each group.

[0042] It can be seen that compared with the blank treatment group, the mRNA levels of metal matrix proteinase genes Mmp3, Mmp13, Adamts4 and Adamts5 in the TNF-α treatment group showed a significant increase, indicating that TNF-α can induce the expression of metal matrix proteinase genes in the chondrocyte cell line ATDC-5, promote the degradation of the extracellular matrix of chondrocytes, and thus accelerate the structural destruction of articular cartilage in the course of osteoarthritis.

[0043] Compared with the TNF-α-treated group, the TNF-α+MSAB-treated group, in which 50 μmol / L MSAB was added while TNF-α was used to induce chondrocyte damage, showed that the mRNA expression levels of Mmp3, Mmp13, Adamts4 and Adamts5 were significantly decreased, indicating that MSAB can inhibit the expression of matrix metalloproteinases in chondrocytes, thereby alleviating the pathological phenotype of osteoarthritis by reducing the degradation of cartilage extracellular matrix.

[0044] In addition, compared with the blank treatment group, the mRNA transcription levels of matrix metalloproteinases Mmp3, Mmp13, and Adamts5 in the MSAB treatment group did not change significantly, while the mRNA transcription level of matrix metalloproteinase Adamts4 changed significantly, indicating that MSAB only inhibits the expression of matrix metalloproteinase Adamts4 under physiological conditions, and has an inhibitory effect on the expression of the four matrix metalloproteinases under pathological conditions, thereby exerting its therapeutic effect on osteoarthritis.

[0045] Example 3: Micro-CT evaluation of the effect of MSAB on cartilage structural damage

[0046] (1) As shown in Figure 4, 30 10-week-old, specific pathogen-free male C57BL / 6 mice weighing 25-30 g were selected and acclimated to the animal room environment for one week. The temperature of the animal room was 22-25°C, and the animals had free access to water and food in their cages. A 12-hour day / night cycle was set. In addition, all animal care and experimental procedures were carried out in accordance with the requirements of the Animal Care and Use Committee of the Laboratory Animal Science Center of the Institute of Advanced Technology, Chinese Academy of Sciences.

[0047] After one week of acclimatization, mice were randomly divided into three groups (10 per group): sham + PBS, DMM + PBS, and DMM + MSAB. Surgery was then performed. In the sham + PBS group, only the medial patellar ligament was incised, exposing the joint cavity, followed by suture of the tissue to the skin. In the DMM + PBS and DMM + MSAB groups, a mouse model of osteoarthritis with destabilization of the medial meniscus (DMM) was established. The specific steps for medial meniscotibial ligament resection were as follows: After anesthesia, immobilization, and sterilization, the medial patellar ligament was incised with a microblade to expose the joint cavity. The intercondylar fat pad was then bluntly dissected to expose the intercondylar area. The medial meniscotibial ligament was then cut with a microblade, and the tissue to the skin was sutured. The operated limb was not immobilized postoperatively, allowing free movement within the cage. Penicillin was injected intraperitoneally to prevent infection.

[0048] Starting at week 4 post-surgery, the drug was administered intra-articularly to all groups of mice. The DMM+MSAB group received MSAB, while the Sham+PBS and DMM+PBS groups received PBS. All groups were treated identically and received equal doses of the drug. Specifically, treatment began at week 4 for four weeks, with injections every three days for a total of eight times, at a dose of 15 mg / kg of mouse body weight. All mice were euthanized at week 16, and the right knee joints were isolated.

[0049] (2) At week 16, micro-computed tomography (micro-CT) examinations were performed on the three groups of mice. Specifically, the knee joints of the mice were fixed in 4% paraformaldehyde for 48 hours, fixed in place with transparent plastic wrap, moistened with 70% ethanol, and then placed in a Micro-CT scanning tube for scanning. Quantitative analysis was performed using analysis software and a three-dimensional reconstruction platform. The detection area was the calcified meniscus and synovial tissue, i.e., osteophytes, and the detection parameters were the volume of the calcified meniscus and synovial tissue.

[0050] Results: Figure 5 shows 3D reconstructed images of the knee joints using Micro-CT, with the images from left to right showing the Sham + PBS treatment group, the DMM + PBS treatment group, and the DMM + MSAB treatment group. Figure 6 shows a statistical graph of knee osteophyte volume, with the vertical axis representing osteophyte volume and the horizontal axis representing group status, in order: the Sham + PBS treatment group, the DMM + PBS treatment group, and the DMM + MSAB treatment group.

[0051] It can be seen that compared with the Sham+PBS treatment group, the formation of knee osteophytes in the mice in the DMM+PBS treatment group was significantly increased, indicating that the medial meniscus modeling of the knee joint caused changes in the microstructure of the mouse knee joint, abnormal bone remodeling, and led to knee instability.

[0052] Compared with the DMM+PBS treatment group, the DMM+MSAB treatment group injected MSAB into the mouse joint cavity, which effectively reduced the formation of osteophytes, indicating that MSAB can effectively alleviate bone destruction and absorption, reduce abnormal bone remodeling, and thus play a role in protecting the bone structure of the knee joint.

[0053] Example 4: Histological Examination of the Effects of MSAB on Cartilage Structural Damage

[0054] The right knee joint tissues of the three groups of mice obtained in step (1) of Example 3 were fixed in 4% paraformaldehyde solution for 3 days, then decalcified in formic acid solution for 1 week, with the solution changed every 3 days. After that, the tissues were dehydrated with gradient ethanol and embedded in paraffin, cut into 5 μm thick sagittal sections, stained with Safranin O-Fast Green, and observed for changes in tissue morphology under an ordinary light microscope to evaluate the degeneration of the mouse knee joint cartilage.

[0055] Results: Figure 7 shows the Safranin O-Fast Green staining images of the right knee joints of mice, from left to right: Sham+PBS treatment group, DMM+PBS treatment group, DMM+MSAB treatment group.

[0056] It can be found that the tibial cartilage surface of the Sham+PBS treatment group was bright and intact, while the cartilage surface of the DMM+PBS treatment group almost disappeared and the bone tissue under the cartilage was exposed. A large amount of matrix was lost and the number of chondrocytes also decreased, indicating that modeling of medial meniscus instability in mice will lead to joint damage and very serious deformity.

[0057] Compared with the DMM+PBS treatment group, the articular cartilage surface of the DMM+MSAB treatment group had fewer defect lesions and retained most of the cartilage tissue. The tibial plateau cartilage surface was continuous, indicating that injecting MSAB into osteoarthritis mice can significantly inhibit matrix loss, improve cartilage layer coloration, reduce chondrocyte hypertrophy and apoptosis, and alleviate the symptoms of cartilage structure damage.

[0058] Example 5: Degenerative Change Scoring of the Effect of MSAB on Cartilage Structural Damage

[0059] Different researchers scored the three sections obtained in Example 4 for degenerative changes, including cartilage area, cartilage degeneration score, synovitis score, and osteophyte score. The cartilage degeneration score was based on the Osteoarthritis Research Society International (OARSI) score. The synovitis score was derived by summing the scores for synovial lining cell proliferation, villous hyperplasia, and the extent of perivascular lymphocyte and monocyte infiltration to assess synovial pathological changes. Synovial lining cell proliferation was scored as 0 for 1-2 layers of cells, 2 for 3-5 layers of cells, and 2 for 6 or more layers. Villous hyperplasia was scored as 0 for absence, 1 for few, scattered, and short villous ... Osteophyte scoring includes the size and maturity of osteophytes. The size of osteophytes is divided into 4 grades: grade 0 normal, grade 1 slightly increased, grade 2 moderately increased, and grade 3 significantly increased. The maturity of osteophytes is divided into 4 grades: grade 0 normal, grade 1 significantly cartilaged, grade 3 mixed bone and cartilage, and grade 4 significantly ossified.

[0060] Results: Figure 8 shows the results of degenerative change scores, where Figures 8A-8E represent the OARSI score, tibial cartilage area scale, synovitis score, osteophyte size score, and osteophyte maturity score, respectively. The horizontal axis represents the groups, which from left to right are the Sham+PBS treatment group, the DMM+PBS treatment group, and the DMM+MSAB treatment group.

[0061] It can be seen that compared with the Sham+PBS treatment group, the OARSI score of mice in the DMM+PBS treatment group increased significantly, while the tibial cartilage area was severely reduced, indicating that the degree of articular cartilage damage at the femur and tibia of mice in the DMM+PBS treatment group increased, wear occurred, and the cartilage became thinner, indicating that they had developed osteoarthritis. In addition, the synovitis score of the DMM+PBS treatment group increased significantly, indicating that the joint capsule of the mice in this group was impacted, causing inflammation of the synovium, indirectly reflecting the development of osteoarthritis. In addition, the osteophyte size score and osteophyte maturity score of the DMM+PBS treatment group also increased significantly, indicating that the biomechanics in the joint cavity of this group of mice was unstable, the support direction changed, and the synovial tissue was stimulated to produce osteophytes. At the same time, the cartilage calcified and had a high degree of maturity. In summary, all indicators directly or indirectly indicate that the DMM+PBS treatment group successfully established an osteoarthritis mouse model with medial meniscus instability.

[0062] Compared with the mice in the DMM+PBS treatment group, the OARSI score, synovitis score, osteophyte size score, and osteophyte maturity score of the mice in the DMM+MSAB treatment group treated with intra-articular injection of MSAB were significantly decreased, and the articular cartilage area was significantly increased, indicating that MSAB can effectively alleviate cartilage damage in the process of osteoarthritis and achieve the purpose of prevention or treatment.

[0063] In summary, the present invention provides a method for preparing a drug for preventing or treating cartilage damage in osteoarthritis using a matrix metalloproteinase inhibitor. Specifically, MSAB is used to inhibit the expression of matrix metalloproteinases in chondrocytes, thereby ameliorating the structural damage to cartilage during osteoarthritis, providing an important guide for the treatment of osteoarthritis.

[0064] The above are only some embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the inventive concept of the present invention, and these all fall within the scope of protection of the present invention.

Claims

1. Application of matrix metalloproteinase inhibitors in the preparation of drugs for preventing or treating osteoarthritis cartilage damage, It is characterized in that The matrix metalloproteinase inhibitor is methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate or a pharmaceutically acceptable salt thereof.

2. Use of the matrix metalloproteinase inhibitor according to claim 1 in the preparation of a drug for preventing or treating osteoarthritis cartilage damage, It is characterized in that The matrix metalloproteinase inhibitor achieves the prevention or treatment of osteoarthritis cartilage damage by inhibiting the expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4 and / or Adamts5.

3. Use of the matrix metalloproteinase inhibitor according to claim 2 in the preparation of a drug for preventing or treating osteoarthritis cartilage damage, It is characterized in that The matrix metalloproteinase inhibitor inhibits the expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4 and / or Adamts5 by inhibiting the activation of the WNT / β-catenin signaling pathway.

4. Use of the matrix metalloproteinase inhibitor according to claim 1 in the preparation of a drug for preventing or treating osteoarthritis cartilage damage, It is characterized in that The matrix metalloproteinase inhibitor achieves the prevention or treatment of osteoarthritis cartilage damage by inhibiting the calcification of the meniscus and / or the regeneration of synovial tissue.

5. Use of the matrix metalloproteinase inhibitor according to any one of claims 1 to 4 in the preparation of a drug for preventing or treating osteoarthritis cartilage damage, It is characterized in that The effective concentration of the matrix metalloproteinase inhibitor is 15 mg / kg body weight.

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