Use of matrix metalloproteinase inhibitors for the preparation of a medicament for the prevention or treatment of osteoarthritic cartilage damage

Abstract

The application relates to the field of geriatric treatment, in particular to application of a matrix metalloproteinase inhibitor, MSAB or a pharmaceutically acceptable salt thereof, in preparation of a medicine for preventing or treating osteoarthritis cartilage injury. The application adopts the MSAB to inhibit expression of matrix metalloproteinase in chondrocytes, reduces destruction of joint cartilage structure, and achieves the effect of preventing or treating osteoarthritis.

Description

Technical Field

[0001] This invention relates to the field of geriatric disease treatment, specifically to the application of a matrix metalloproteinase inhibitor in the preparation of drugs for the prevention or treatment of cartilage damage in osteoarthritis. Background Technology

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

[0003] Therefore, there is an urgent need to develop a drug that can effectively cure osteoarthritis. Drug development is based on understanding and exploring the molecular mechanisms of the disease, but little is known about the occurrence and development of osteoarthritis, which means that no effective treatment for osteoarthritis has yet been developed. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and solve at least one of the defects in the above-mentioned background art.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] This invention provides the use of a matrix metalloproteinase inhibitor in the preparation of a drug for the prevention or treatment of cartilage damage in osteoarthritis, wherein the matrix metalloproteinase inhibitor is methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the matrix metalloproteinase inhibitors achieve the prevention or treatment of cartilage damage in osteoarthritis by inhibiting the expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4 and / or Adamts5.

[0008] In some embodiments, the matrix metalloproteinase inhibitors inhibit the expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4, and / or Adamts5 by inhibiting the activation of the WNT / β-catenin signaling pathway.

[0009] In some embodiments, the matrix metalloproteinase inhibitors achieve the prevention or treatment of cartilage damage in osteoarthritis by inhibiting meniscalcification and / or synovial tissue regeneration.

[0010] In some embodiments, the effective concentration of the matrix metalloproteinase inhibitor is 15 mg / kg body weight.

[0011] The beneficial effect of this invention is that methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate is used as a potential small drug molecule in the treatment of cartilage damage in osteoarthritis. This drug effectively inhibits cartilage structural damage in the progression of osteoarthritis by suppressing the expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4, and Adamts5, providing important guidance for the treatment of osteoarthritis. Attached Figure Description

[0012] Figure 1 The chemical structural formula of methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate is given.

[0013] Figure 2 shows the qPCR detection results of downstream genes of the β-catenin signaling pathway in ATDC-5 cells in one embodiment. Figure 2A and 2B These represent the mRNA expression levels of Axin2 and Dkk1, respectively.

[0014] Figure 3 shows the qPCR detection results of extracellular matrix-related molecules in ATDC-5 cells in one embodiment. Figures 3A to 3D These represent the mRNA transcription levels of the matrix metalloproteinase genes Mmp3, Mmp13, Adamts4, and Adamts5, respectively.

[0015] Figure 4 This is a flowchart illustrating the mouse modeling and treatment of osteoarthritis in one embodiment.

[0016] Figure 5 This is a 3D reconstructed image of a mouse knee joint using Micro-CT in one embodiment;

[0017] Figure 6 A statistical diagram of osteophyte volume in the mouse knee joint of one embodiment;

[0018] Figure 7 This is a Safranin O-Fix Green stained image of a mouse knee joint in one embodiment;

[0019] Figure 8 is a scoring chart of knee joint degenerative changes in mice in one embodiment, wherein... Figures 8A-8E These represent the OARSI score, cartilage area, synovitis score, osteophyte size, and osteophyte maturity, respectively. Detailed Implementation

[0020] The technical solution of this patent will be further described in detail below with reference to specific embodiments. It should be noted that the following detailed descriptions are exemplary and 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 one of ordinary skill in the art to which this application pertains.

[0021] Previous studies have revealed that multiple signaling pathways, such as Indianhedgehog and TGF-β, can participate in the regulation of osteoarthritis pathology by directly or indirectly affecting anabolism and catabolism in cartilage. Among these, the Wnt / β-catenin signaling pathway, as an important cellular signaling pathway, has been shown to be a significant predisposing factor for osteoarthritis due to its abnormal activity. Research indicates 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 an important pathological phenotype in the knee, hip, temporomandibular joint, and intervertebral disc joints.

[0022] In studies of the molecular mechanisms of the Wnt / β-catenin signaling pathway, key components have been identified, including Wnt protein, β-catenin, Frizzled receptor, and LDL receptor-associated proteins. Under normal conditions, the Wnt pathway is inactive, with β-catenin being phosphorylated and degraded. When Wnt protein binds to Frizzled receptor and LDL receptor-associated proteins, Axin and GSK-3β are activated, inhibiting β-catenin degradation and leading to its accumulation in the cytoplasm and entry into the nucleus. In the nucleus, β-catenin binds to TCF / LEF to form a complex, thereby activating the expression of downstream genes in the Wnt / β-catenin signaling pathway. Mouse and human osteoarthritis models have demonstrated that significant upregulation of WISP-1 protein in articular cartilage and synovial tissue, along with upregulation of matrix metalloproteinases (MMPs) and agglutinases in chondrocytes and macrophages, all promote articular cartilage damage.

[0023] The following examples use methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate (Methyl3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(dimethylamino)benzoate, MSAB) as a potential small molecule drug for the treatment of cartilage damage in osteoarthritis. Its structural formula is as follows: Figure 1As shown in the figure. Currently, MSAB, as an anti-tumor research drug, has shown an inhibitory effect on the growth of Wnt-dependent cancer cells. Its mechanism is related to the binding of MSAB to β-catenin, a key protein in the Wnt / β-catenin signaling pathway. The binding of the two can promote the ubiquitination and degradation of β-catenin, reduce its stability and activity, and thus inhibit the activity of the Wnt / β-catenin signaling pathway.

[0024] Furthermore, the following examples used ATDC5 cells as in vitro experimental cells for studying osteoarthritis treatment. ATDC5 cells are a mouse fibroblast cell line commonly used in bone development research. Obtained 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 formation of cartilage and bone during embryonic development, and therefore they are widely used in research on bone development, cartilage, and bone diseases.

[0025] Meanwhile, the following examples used tumor necrosis factor-α (TNF-α) to induce activation of the β-catenin signaling pathway and expression of matrix metalloproteinase-related genes in ATDC5 cells in vitro to study the mechanism by which MSAB affects osteoarthritis. TNF-α is an inflammatory mediator that plays an important role in the occurrence and development of osteoarthritis. Large amounts of TNF-α are present in the joints of osteoarthritis patients. These TNF-α molecules stimulate synovial cells and chondrocytes to secrete a series of inflammatory factors and enzymes, such as IL-1β, IL-6, and MMPs, further exacerbating the condition. Furthermore, TNF-α can promote the infiltration and activation of inflammatory cells, leading to the destruction of articular cartilage and bone resorption, thereby accelerating the development of osteoarthritis. Therefore, TNF-α has become an important tool in in vitro research on osteoarthritis.

[0026] The biological materials used in this invention were sourced as follows: ATDC-5 chondrocyte cell line was purchased from American Type Culture Collection; DMEM 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 Beyotime Biotechnology Co., Ltd.; CGRP antibody was purchased from Abcam; primers used for qPCR were purchased from Sangon Biotech (Shanghai) Co., Ltd.; the LABORAS platform was purchased from Metris; and C57BL / 6 mice were purchased from Jiangsu Jicui Pharmaceutical Co., Ltd.

[0027] It should be understood that all statistical comparisons in the following examples were performed using PrismGraphPad statistical software. In addition, all data were compared between different groups using one-way ANOVA and Tukey's multiple comparison test was performed. A p-value < 0.05 was considered statistically significant. The results are expressed as mean ± SD.

[0028] This invention provides the application of a matrix metalloproteinase inhibitor (MSAB) in the preparation of drugs for the prevention or treatment of cartilage damage in osteoarthritis. Specifically, MSAB is used to reduce osteophyte formation and histopathological scores in osteoarthritis mice, thereby alleviating cartilage structural damage and providing 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 inhibiting the expression of matrix metalloproteinase-related genes.

[0029] The present invention will be further illustrated below through specific experimental examples.

[0030] Example 1: Effects of MSAB on downstream genes of the β-catenin signaling pathway in chondrocytes

[0031] (1) ATDC5 cells in good growth condition were seeded in 12-well culture plates and cultured until the cell density reached 70-80%. Then they were divided into four groups: blank treatment group, MSAB treatment group, TNF-α treatment group, and TNF-α+MSAB treatment group, with 3 replicates for each group.

[0032] 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 treated with complete medium containing 20 ng / mL TNF-α for 9 h, and the TNF-α+MSAB treatment group was first treated with complete medium containing 20 ng / mL TNF-α for 9 h, and then treated with 50 μmol / L MSAB for 3 h.

[0033] (2) Total RNA was extracted from the four groups of cells obtained in step (1), and real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the downstream genes Axin2 and Dkk1 of the β-catenin signaling pathway in chondrocytes according to the kit instructions.

[0034] Results: Figure 2 shows the qPCR detection results of downstream genes of the β-catenin signaling pathway in ATDC-5 cells, where... Figure 2A and 2BThe mRNA expression levels of Axin2 and Dkk1 are represented by the vertical axis, which represents the fold increase in gene upregulation with β-Actin as the control gene, and the horizontal axis represents the groups, namely the blank treatment group, MSAB treatment group, TNF-α treatment group, and TNF-α+MSAB treatment group. The expression level of Axin2 or Dkk1 in the blank treatment group is set to 1.

[0035] 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 upregulation of the mRNA expression of Axin2 and Dkk1, target genes of the β-catenin signaling pathway.

[0036] Compared with the blank treatment group, the mRNA expression of Axin2 and Dkk1 in the MSAB treatment group was significantly reduced, indicating that under physiological conditions, MSAB can inhibit the expression of downstream genes Axin2 and Dkk1 of the β-catenin signaling pathway.

[0037] Compared to the TNF-α treatment group, the TNF-α+MSAB treatment group, after being treated with TNF-α, was injected with 50 μmol / L MSAB. At this time, the mRNA expression levels of Axin2 and Dkk1 were significantly reduced, indicating that MSAB can inhibit the upregulation of Axin2 and Dkk1 induced by TNF-α, thereby inhibiting the activity of the β-catenin signaling pathway in ATDC-5 cells and alleviating the progression of osteoarthritis.

[0038] Example 2: Effects of MSAB on the extracellular matrix of chondrocytes

[0039] 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 matrix metalloproteinase genes Mmp3, Mmp13, Adamts4, and Adamts5 in chondrocytes according to the kit instructions.

[0040] Results: Figure 3 shows the qPCR detection results of extracellular matrix-related molecules in ATDC-5 cells, among which... Figures 3A to 3D The mRNA transcription levels of matrix metalloproteinase genes Mmp3, Mmp13, Adamts4, and Adamts5 are represented, respectively. The vertical axis represents the fold upregulation of genes with β-Actin as the control gene, and the horizontal axis represents the groups, namely blank treatment group, MSAB treatment group, TNF-α treatment group, and TNF-α+MSAB treatment group. β-Actin was used as an internal control in each group.

[0041] It can be seen that, compared with the blank treatment group, the mRNA levels of matrix metalloproteinase genes Mmp3, Mmp13, Adamts4 and Adamts5 were significantly increased in the TNF-α treatment group, indicating that TNF-α can induce the expression of matrix metalloproteinase 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.

[0042] Compared to the TNF-α treatment group, the TNF-α+MSAB treatment group, which incorporated 50 μmol / L MSAB while inducing chondrocyte damage with TNF-α, showed a significant decrease in the mRNA expression levels of Mmp3, Mmp13, Adamts4, and Adamts5. This indicates that MSAB can inhibit the expression of matrix metalloproteinases in chondrocytes, thereby reducing the degradation of the extracellular matrix in chondrocytes and alleviating the pathological phenotype of osteoarthritis.

[0043] Furthermore, compared to 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. This indicates that MSAB only inhibits the expression of matrix metalloproteinase Adamts4 under physiological conditions, but inhibits the expression of all four matrix metalloproteinases under pathological conditions, thereby exerting its therapeutic effect on osteoarthritis.

[0044] Example 3: Micro-CT assessment of the impact of MSAB on cartilage structure damage

[0045] (1) As Figure 4 As shown, 30 ten-week-old male C57BL / 6 mice, weighing 25-30g and free from specific pathogens, were selected and acclimatized to the animal facility environment for one week. The temperature in the animal facility was maintained at 22-25℃, and the animals had free access to water and food in their cages. A 12-hour / 12-hour day / night cycle was implemented. Furthermore, all animal care and experimental procedures followed the requirements of the Animal Management and Use Committee of the Laboratory Animal Science Center, Institute of Advanced Technology, Chinese Academy of Sciences.

[0046] After a week of acclimatization, mice were randomly divided into three groups—Sham+PBS treatment group, DMM+PBS treatment group, and DMM+MSAB treatment group, with 10 mice in each group, and underwent surgery. In the Sham+PBS treatment group, only the medial side of the patellar ligament was incised to expose the joint cavity before suturing the tissue and skin. In the DMM+PBS and DMM+MSAB treatment groups, a mouse model of medial meniscus instability (DMM) osteoarthritis was established. The specific steps of the medial meniscectomy and tibial ligament resection were as follows: After anesthesia, fixation, and disinfection, the medial side of the patellar ligament was incised with a microsurgical blade to expose the joint cavity. Then, the intercondylar fat pad of the femur was bluntly dissected to expose the intercondylar region. The medial meniscectomy and tibial ligament were then severed with a microsurgical blade, and the tissue and skin were sutured. Postoperatively, the operated limb was not fixed, and the mice were allowed free movement within the cage. Penicillin was injected intraperitoneally to prevent infection.

[0047] Starting at week 4 post-surgery, mice in all groups underwent intra-articular injections of the drug. The DMM+MSAB treatment group received MSAB, while the Sham+PBS treatment group and the DMM+PBS treatment group received PBS. All groups received the same administration method and dosage. Specifically, all three groups were treated for 4 weeks starting at week 4, with injections every three days for a total of 8 injections, administered intra-articularly at a dose of 15 mg / kg mouse body weight. All mice were euthanized at week 16, and the right knee joint was dissected.

[0048] (2) At week 16, mice in the three groups underwent micro-computed tomography (micro-CT) examinations. Specifically, the mouse knee joints were fixed in 4% paraformaldehyde for 48 hours, then secured 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 areas were calcified menisci and synovial tissue, i.e., osteophytes, and the detection parameter was the volume of calcified menisci and synovial tissue.

[0049] result: Figure 5 The images show 3D reconstructed images of the knee joint from Micro-CT, from left to right: Sham+PBS treatment group, DMM+PBS treatment group, and DMM+MSAB treatment group. Figure 6 The chart shows the volume of osteophytes in the knee joint, with the vertical axis representing the osteophyte volume and the horizontal axis representing the group, namely the Sham+PBS treatment group, the DMM+PBS treatment group, and the DMM+MSAB treatment group.

[0050] It can be seen that, compared with the Sham+PBS treatment group, the DMM+PBS treatment group showed a significant increase in knee osteophyte formation, indicating that the medial meniscus modeling of the knee joint caused changes in the microstructure of the knee joint in mice, resulting in abnormal bone remodeling and knee instability.

[0051] Compared with the DMM+PBS treatment group, the DMM+MSAB treatment group, which injected MSAB into the joint cavity of mice, effectively reduced the formation of osteophytes. This indicates that MSAB can effectively alleviate bone destruction and resorption, reduce abnormal bone remodeling, and thus play a role in protecting the bone structure of the knee joint.

[0052] Example 4: Histological examination of the effects of MSAB on cartilage structure damage

[0053] 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, and then decalcified in formic acid solution for 1 week, with the solution changed every 3 days. After that, the tissues were dehydrated in gradient ethanol and embedded in paraffin, cut into 5 μm thick sagittal sections, stained with safranin O-fast green and observed under a light microscope to evaluate the changes in tissue morphology in the mouse knee joint cartilage.

[0054] result: Figure 7 Images of Safranin O-Fix Green staining on the right knee joint of mice are shown. From left to right, they represent the Sham+PBS treatment group, the DMM+PBS treatment group, and the DMM+MSAB treatment group.

[0055] It can be observed that the tibial cartilage surface of the Sham+PBS treatment group is shiny and intact, while the cartilage surface of the DMM+PBS treatment group is almost gone, exposing the bone tissue in the subchondral layer. A large amount of matrix is ​​lost, and the number of chondrocytes is also reduced. This indicates that inducing medial meniscus instability modeling in mice will lead to joint destruction and severe deformity.

[0056] Compared to the DMM+PBS treatment group, the DMM+MSAB treatment group showed fewer defects and lesions on the articular cartilage surface and preserved 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 staining, reduce chondrocyte hypertrophy and apoptosis, and alleviate symptoms of cartilage structural damage.

[0057] Example 5: Degenerative Changes Scoring of the Effects of MSAB on Cartilage Structure Damage

[0058] The three groups of slides obtained in Example 4 were scored for degenerative changes by different researchers. The scores included cartilage area, cartilage degeneration, synovitis, and osteophyte formation. The cartilage degeneration scoring criteria referenced the Osteoarthritis Research Society International (OARSI) scoring system. The synovitis score was the sum of scores for the degree of synovial lining cell proliferation, villous proliferation, and perivascular lymphocyte and monocyte infiltration, used to evaluate pathological changes in the synovium. Specifically, the scoring criteria for synovial lining cell proliferation were: 0 points for 1-2 layers of cells, 2 points for 3-5 layers, and 2 points for 6 layers or more; for villous proliferation, 0 points for absence, 1 point for few, scattered, and short villous cells, 2 points for finger-like projection, and 3 points for both finger-like projection and diffuse reflection; and for perivascular lymphocyte and monocyte infiltration, 0 points for normal, and 5 points for significant cell infiltration mixed with lymphoid follicles. The osteophyte score includes the size and maturity of the osteophytes. The size of the 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 the osteophytes is divided into 4 grades: grade 0 normal, grade 1 significant chondrification, grade 3 mixed bone and cartilage, and grade 4 significant ossification.

[0059] Results: Figure 8 shows the degenerative change scoring results, in which Figures 8A-8E The scores represent the OARSI score, tibial cartilage area scale, synovitis score, osteophyte size score, and osteophyte maturity score, respectively. The horizontal axis represents the group, from left to right: Sham+PBS treatment group, DMM+PBS treatment group, and DMM+MSAB treatment group.

[0060] As can be seen, compared with the Sham+PBS treatment group, the OARSI score of mice in the DMM+PBS treatment group was significantly increased, while the tibial cartilage area was severely reduced. This indicates that the degree of articular cartilage damage in the femur and tibia of mice in the DMM+PBS treatment group was increased, with wear and thinning of the cartilage, indicating the development of osteoarthritis. Furthermore, the synovitis score in the DMM+PBS treatment group was significantly increased, indicating that the joint capsule of these mice was impacted, leading to inflammation of the synovium, indirectly reflecting the development of osteoarthritis. In addition, the osteophyte size and maturity scores in the DMM+PBS treatment group were also significantly increased, indicating that the joint cavity of these mice was biomechanically unstable, with changes in the support direction, stimulating the synovial tissue to produce osteophytes, while the cartilage showed calcification and high maturity. In summary, all indicators directly or indirectly demonstrate that the DMM+PBS treatment group successfully established a mouse model of osteoarthritis with medial meniscus instability.

[0061] Compared with the DMM+PBS treatment group, the DMM+MSAB treatment group mice treated with intra-articular injection of MSAB showed significantly lower OARSI scores, synovitis scores, osteophyte size scores, and osteophyte maturity scores, and significantly increased articular cartilage area. This indicates that MSAB can effectively alleviate cartilage damage in the process of osteoarthritis and achieve the purpose of prevention or treatment.

[0062] In summary, this invention provides the application of a matrix metalloproteinase inhibitor (MSAB) in the preparation of drugs for the prevention or treatment of cartilage damage in osteoarthritis. Specifically, MSAB is used to inhibit the expression of matrix metalloproteinases in chondrocytes, thereby improving the destruction of cartilage structure during the course of osteoarthritis and providing an important reference for guiding the treatment of osteoarthritis.

[0063] The above descriptions are merely some embodiments of the present invention. Those skilled in the art can make various modifications and improvements 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. Use of a matrix metalloproteinase inhibitor for the manufacture of a medicament for the prevention or treatment of osteoarthritic cartilage damage, characterized in that, The matrix metalloproteinase inhibitor is methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate or a pharmaceutically acceptable salt thereof; The matrix metalloproteinase inhibitor achieves prevention or treatment of osteoarthritic cartilage damage by inhibiting expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4 and / or Adamts5; Or, the matrix metalloproteinase inhibitor achieves prevention or treatment of osteoarthritic cartilage damage by inhibiting calcification of meniscus and / or neogenesis of synovial tissue.

2. Use of the matrix metalloproteinase inhibitor according to claim 1 for the manufacture of a medicament for the prevention or treatment of osteoarthritic cartilage damage, characterized in that, The matrix metalloproteinase inhibitor achieves inhibition of expression of matrix metalloproteinases Mmp3, Mmp13, Adamts4 and / or Adamts5 by inhibiting activation of WNT / β-catenin signaling pathway.

3. Use of a matrix metalloprotease inhibitor according to claim 1 or 2 for the manufacture of a medicament for the prevention or treatment of osteoarthritic cartilage damage, characterized in that, The effective concentration of the matrix metalloproteinase inhibitor is 15 mg / kg of body weight.

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