CN116942652A - Application of matrix metalloproteinase inhibitor in preparing medicine for preventing or treating osteoarthritis cartilage injury - Google Patents
Application of matrix metalloproteinase inhibitor in preparing medicine for preventing or treating osteoarthritis cartilage injury Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The application relates to the field of senile disease treatment, in particular to application of a matrix metalloproteinase inhibitor MSAB or pharmaceutically acceptable salt thereof in preparing a medicine for preventing or treating osteoarthritis cartilage injury. The application adopts MSAB to inhibit the expression of matrix metalloproteinase in cartilage cells, reduces the damage of articular cartilage structure, and achieves the effect of preventing or treating osteoarthritis.
Description
Technical Field
The application relates to the field of senile disease treatment, in particular to application of a matrix metalloproteinase inhibitor in preparing a medicine for preventing or treating osteoarthritis cartilage injury.
Background
Osteoarthritis is a chronic degenerative disease caused by progressive destruction of articular cartilage and subchondral bone tissue, and its pathological features are articular cartilage destruction, restricted movement, osteophyte formation, chronic pain, etc. Currently, the treatment route of osteoarthritis is mainly artificial joint replacement, but there are some problems with this approach: the risk of surgery is high, such as infection, hemorrhage, thrombosis, etc.; complications such as loosening and dislocation of the prosthesis can occur after operation; the prosthesis has a limited life and may need to be replaced by a surgical operation again; the treatment requires a large amount of medical equipment and medical staff to participate, the cost is high, and a large burden is caused on the economy of patients.
Therefore, there is a great need for developing a medicament which can effectively cure osteoarthritis. While the development of drugs is based on understanding and exploring the molecular mechanism of the disease, little is known about the occurrence and development of osteoarthritis, so that no drugs capable of effectively treating osteoarthritis have been developed nowadays.
Disclosure of Invention
The present application aims to overcome the deficiencies of the prior art and to solve at least one of the drawbacks of the prior art described above.
In order to achieve the above purpose, the present application provides the following technical solutions:
the application provides an application of a matrix metalloproteinase inhibitor in preparing a medicine for preventing or treating osteoarthritis cartilage injury, wherein the matrix metalloproteinase inhibitor is methyl3- { [ (4-methylphenyl) sulfonyl ] amino } benzoate or a pharmaceutically acceptable salt thereof.
In some embodiments, the matrix metalloproteinase inhibitor effects prevention or treatment of an osteoarthritic cartilage injury by inhibiting expression of matrix metalloproteinases Mmp3, mmp13, adams 4 and/or adams 5.
In some embodiments, the matrix metalloproteinase inhibitor effects inhibition of matrix metalloproteinase Mmp3, mmp13, adams 4, and/or adams 5 expression by inhibiting activation of WNT/beta-catenin signaling pathway.
In some embodiments, the matrix metalloproteinase inhibitor effects the prevention or treatment of osteoarthritis cartilage damage by inhibiting calcification of the meniscus and/or neogenesis of synovial tissue.
In some embodiments, the effective concentration of the matrix metalloproteinase inhibitor is 15mg/kg body weight.
The application has the beneficial effects that the 3- { [ (4-methylphenyl) sulfonyl ] amino } methyl benzoate is used as a potential drug small molecule and is applied to the treatment scene of osteoarthritis cartilage injury. The medicine can effectively inhibit cartilage structure injury in the process of osteoarthritis by inhibiting the expression of matrix metalloproteinases Mmp3, mmp13, adamps 4 and adamps 5, and provides an important reference for guiding treatment of osteoarthritis.
Drawings
FIG. 1 is a chemical formula of methyl3- { [ (4-methylphenyl) sulfonyl ] amino } benzoate;
FIG. 2 is a qPCR assay of a gene downstream of the β -catenin signaling pathway in ATDC-5 cells in one example, wherein FIGS. 2A and 2B show mRNA expression levels of Axin2 and Dkk1, respectively;
FIG. 3 shows the qPCR detection of the extracellular matrix-related molecules of ATDC-5 cells in one example, wherein FIGS. 3A to 3D show the mRNA transcription levels of the metalloproteinase genes Mmp3, mmp13, adams 4, adams 5, respectively;
FIG. 4 is a flow chart of modeling and treatment of an osteoarthritis mouse in one embodiment;
FIG. 5 is a 3D reconstructed image of a mouse knee Micro-CT in one embodiment;
FIG. 6 is a statistical plot of knee joint osteophyte volumes in a mouse in one embodiment;
FIG. 7 is an O-fast green stained image of a mouse knee safranin in one embodiment;
fig. 8 is a graph of a score of degenerative changes in the knee joint of a mouse in an embodiment, wherein fig. 8A-8E represent OARSI score, cartilage area, synovitis score, bone tag size, bone tag maturity, respectively.
Detailed Description
The technical solutions of the present patent will be described in further detail below with reference to specific embodiments, and it should be noted that the following detailed description is exemplary, and is intended to provide further explanation of the present application. Unless defined otherwise, 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 belongs.
In previous studies, it was found that a plurality of signal pathways such as Indianhedgehog, TGF-. Beta.can be involved in the pathological process control of osteoarthritis by directly or indirectly affecting anabolism and catabolism in cartilage. Among them, the Wnt/β -catenin signaling pathway is an important cell signaling pathway, and its abnormal activity has been demonstrated to be an important susceptibility factor for osteoarthritis. Studies have shown that aberrant activation of Wnt/β -catenin signaling in chondrocytes leads to reduced articular cartilage thickness, degradation of cartilage matrix, and hypertrophy and apoptosis of chondrocytes. At the same time, aberrant activation of Wnt/β -catenin signaling pathway is also an important pathological phenotype in knee, hip, mandibular and intervertebral disc joints.
In the study of the related molecular mechanisms of the Wnt/beta-catenin signaling pathway, key components of the pathway are found to include Wnt proteins, beta-catenin, frizzled receptors, LDL receptor-related proteins and the like. Normally, the Wnt pathway is inactive and β -catenin is phosphorylated and degraded. When the Wnt protein is combined with Frizzled receptor and LDL receptor related protein, axin and GSK-3 beta are activated, so that degradation of beta-catenin is inhibited, and the beta-catenin is accumulated in cytoplasm and enters nucleus. In the nucleus, β -catenin binds to TCF/LEF to form a complex, which in turn activates downstream gene expression of Wnt/β -catenin signaling pathway. The mouse and human osteoarthritis models prove that the significant up-regulated expression of WISP-1 protein in articular cartilage and synovial tissue, and the up-regulated expression of matrix metalloproteinase (MatrixMetalloproteinase, MMPs) and aggrecanase in chondrocytes and macrophages can promote articular cartilage injury.
The following example uses Methyl3- { [ (4-methylphenyl) sulfonyl ] amino } benzoate (Methyl 3- (1H-pyrrrolo [2,3-b ] pyridin-5-yl) -4- (dimethyllamino) benzoate, MSAB) as a potential small molecule drug for the treatment of osteoarthritis cartilage injury, the structural formula of which is shown in FIG. 1. At present, MSAB is taken as an anti-tumor research drug, and shows the growth inhibition effect on Wnt-dependent cancer cells, the mechanism of the MSAB is related to the combination of MSAB and beta-catenin which is a key protein in a Wnt/beta-catenin signal path, and the combination of the MSAB and beta-catenin can promote ubiquitination and degradation of the beta-catenin, reduce the stability and activity of the beta-catenin, and further inhibit the activity of the Wnt/beta-catenin signal path.
In addition, 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 skeletal development studies, obtained from mouse embryonic skeletal muscle tissue, which can divide multiple times in vitro and differentiate into chondrocytes and bone cells. The differentiation pathway of ATDC5 cells is similar to the process of cartilage and bone formation in embryonic development and is therefore widely used in the study of skeletal development, cartilage and bone diseases.
Meanwhile, the following examples use tumor necrosis factor-alpha (TNF-alpha) to induce activation of beta-catenin signaling pathway and expression of matrix metalloproteinase-related gene in ATDC5 cells in vitro to investigate the mechanism of action of MSAB on osteoarthritis. TNF- α is an inflammatory mediator that plays an important role in the development and progression of osteoarthritis. Within the joints of osteoarthritis patients, there is a large amount of TNF- α that stimulates synovial and chondrocytes to secrete a range of inflammatory factors and enzymes, such as IL-1 beta, IL-6, MMPs, etc., further exacerbating the arthritic condition. In addition, TNF- α can also promote infiltration and activation of inflammatory cells, resulting in destruction of articular cartilage and resorption of bone, thereby accelerating the development of osteoarthritis. TNF- α has therefore become an important tool in vitro studies of osteoarthritis.
The biological material source of the application is as follows: chondrocyte line ATDC-5 was purchased from Americantypeculture collection; DMEM medium, fetal bovine serum, penicillin, streptomycin, trypsin was purchased from Gibico corporation; MSAB, TNF- α available from Selleckchem; NGF antibodies were purchased from Shanghai Biyun biotechnology Co., ltd; CGRP antibodies were purchased from Abcam corporation; primers for qPCR were purchased from Shanghai, inc.; the LABORAS platform is purchased from Metris; c57BL/6 mice were purchased from Jiangsu province, jieXtensii Karsch Biotech Co.
It should be understood that all statistical comparisons in the examples below were performed using prism graphpad statistical software, and that all data were compared in different groups using one-way anova, and Tukey multiple comparison tests were performed, with differences being considered statistically significant when P < 0.05, and the results expressed as mean+ -SD.
The application provides an application of a matrix metalloproteinase inhibitor in preparing medicines for preventing or treating osteoarthritis cartilage injury, namely, MSAB is adopted to reduce osteophyte hyperplasia and histopathological score of an osteoarthritis mouse, cartilage structure injury is relieved, and further, references are provided for treating and preventing osteoarthritis, and the mechanism of the matrix metalloproteinase inhibitor is related to activation of MSAB inhibition beta-catenin signal channel and inhibition of expression of matrix metalloproteinase related genes.
The application is further illustrated by the following specific experimental examples.
Example 1: effect of MSAB on downstream genes of β -catenin signaling pathway in chondrocytes
(1) ATDC5 cells with good growth status were plated in 12-well plates for culture until cell density reached 70-80%, and then divided into four groups, blank treatment group, MSAB treatment group, TNF- α treatment group, TNF- α+msab treatment group, each group being repeated for 3 wells.
According to the grouping requirements, the blank treatment group is injected with phosphate buffer (PhosphateBufferedSaline, PBS), the MSAB treatment group is added with 50 mu mol/LMSAB treatment cells for 3h, the TNF-alpha treatment group is replaced with complete medium treatment 9h containing 20 ng/mLTNF-alpha, the TNF-alpha+MSAB treatment group is replaced with complete medium treatment 9h containing 20 ng/mLTNF-alpha, and 50 mu mol/LMSAB treatment cells are added for 3h.
(2) And (3) extracting total RNA from the four groups of cells obtained in the step (1), and carrying out a Real-time fluorescent quantitative polymerase chain reaction (Real-TimeQuantitativePolymeraseChainReaction, RT-qPCR) experiment on downstream genes Axin2 and Dkk1 of a beta-catenin signal path in the chondrocytes according to a kit instruction.
Results: FIG. 2 shows the qPCR detection results of the gene downstream of the β -catenin signal pathway in ATDC-5 cells, wherein FIGS. 2A and 2B show mRNA expression levels of Axin2 and Dkk1, respectively, the ordinate shows the gene up-regulation factor using β -action as a control gene, and the abscissa shows the group, which is in turn a blank treatment group, MSAB treatment group, TNF- α treatment group, TNF- α+MSAB treatment group, and the Axin2 or Dkk1 expression level of the blank treatment group is set to 1.
It can be seen that the mRNA expression levels of Axin2 and Dkk1 were significantly increased in the TNF- α treated group compared to the blank treated group, indicating that the injection of TNF- α into the chondrocyte line ATDC5 as a positive control induced up-regulation of mRNA expression of the target genes Axin2 and Dkk1 of the β -catenin signaling pathway.
Compared with the blank treatment group, the mRNA expression of Axin2 and Dkk1 of the MSAB treatment group is obviously reduced, which indicates that under physiological conditions, MSAB can inhibit the expression of Axin2 and Dkk1 of downstream genes of a beta-catenin signal pathway.
Compared with the TNF-alpha treatment group, the TNF-alpha+MSAB treatment group is also injected with 50 mu mol/LMSAB after the TNF-alpha treatment of the cells, and the mRNA expression level of Axin2 and Dkk1 is obviously reduced at the moment, which proves that the MSAB can inhibit the up-regulation of the expression of genes Axin2 and Dkk1 induced by TNF-alpha, further inhibit the activity of beta-catenin signal channels in ATDC-5 cells and relieve the osteoarthritis process.
Example 2: effect of MSAB on extracellular matrix of chondrocytes
Total RNA extraction was performed on the four groups of cells obtained in step (1) of example 1, and RT-qPCR experiments were performed on the metal matrix protease genes Mmp3, mmp13, adams 4, adams 5 in chondrocytes according to the kit instructions.
Results: FIG. 3 shows the qPCR detection results of extracellular matrix-related molecules of ATDC-5 cells, wherein FIGS. 3A to 3D show mRNA transcription levels of the metal matrix protease genes Mmp3, mmp13, adams 4, adams 5, respectively, the ordinate shows the gene up-regulation fold with β -action as a control gene, and the abscissa shows the groups, which are in turn blank treatment group, MSAB treatment group, TNF- α treatment group, TNF- α+MSAB treatment group, each group taking β -action as an internal reference.
It can be seen that the mRNA levels of the matrix metalloproteinase genes mmap 3, mmap 13, adams 4 and adams 5 exhibited a significant increase in TNF- α treated groups compared to the blank treated groups, indicating that TNF- α can induce expression of the matrix metalloproteinase gene in the chondrocyte ATDC-5, promote extracellular matrix degradation of chondrocytes, and further accelerate structural destruction of articular cartilage in the course of osteoarthritis disease.
Compared with the TNF-alpha treatment group, the TNF-alpha+MSAB treatment group is added with 50 mu mol/LMSAB while adopting TNF-alpha to induce the damage of the chondrocytes, and the mRNA level expression of Mmp3, mmp13, adams 4 and adams 5 can be detected to be obviously reduced, which proves that the MSAB can inhibit the expression of matrix metalloproteinase in the chondrocytes, thereby reducing the pathological phenotype of osteoarthritis by reducing the degradation of extracellular matrix of the chondrocytes.
In addition, compared with the blank treatment group, the mRNA transcription level of the matrix metalloproteinases Mmp3, mmp13 and adams 5 in the MSAB treatment group is not changed obviously, but the mRNA transcription level of the matrix metalloproteinase adams 4 is changed obviously, which proves that the MSAB only inhibits the expression of the matrix metalloproteinase adams 4 under physiological conditions, and has an inhibiting effect on the expression of four matrix metalloproteinases under pathological conditions, thereby playing a role in treating osteoarthritis.
Example 3: micro-CT examination evaluation of influence of MSAB on cartilage structural damage
(1) As shown in FIG. 4, 30 male C57BL/6 mice, 25-30g in weight, that are 10 weeks old and have no specific pathogen, were selected and adapted for one week in an animal room environment. Wherein the temperature of the animal house is 22-25deg.C, and the animal can freely draw water and food in the cage, and set for 12/12 hours daily overnight cycle. In addition, all animal care and experimental procedures were conducted following the requirements of the animal management and use committee of the national academy of sciences advanced technology laboratory animal science center.
After one week of adaptation, the mice were randomly divided into three groups, sham+pbs, dmm+pbs, dmm+msab, 10 per group, and surgery was performed. Wherein, the sham+pbs-treated group only cuts the inner side of the patellar ligament, and tissues and skin are sutured after the joint cavity is exposed, and the dmm+pbs-treated group and the dmm+msab-treated group construct an osteoarthritis mouse model of medial meniscus instability (DestabilizationoftheMedialMeniscus, DMM). The specific procedure for medial meniscus tibial ligament resection is as follows, after the mice are anesthetized, fixed, sterilized, the medial patellar ligament is cut with a microblade, the articular cavity is exposed, then the fat pad between the femoral condyles is blunt separated, the intercondylar area is exposed, the medial meniscus tibial ligament is picked up with a microblade, and the tissues and skin are sutured. The operative limb is not fixed after the operation, the cage moves freely, and penicillin is injected into the abdominal cavity to prevent infection.
The intra-articular injection dosing of each group of mice was started at week 4 post-surgery, with the dmm+msab-treated group injected with MSAB, the sham+pbs-treated group and the dmm+pbs-treated group injected with PBS. The same dosing regimen was used for each group of mice and an equal dose of the agent was administered, specifically, three groups were each injected every three days for 4 weeks, 8 total injections, and joint cavity injections were performed at 15mg/kg of mouse body weight, starting at week 4. All mice were euthanized at week 16 and the right knee joint was isolated.
(2) Three groups of mice were examined by Micro-computed tomography (Micro-CT) at week 16, specifically, the knee joints of the mice were fixed in 4% paraformaldehyde for 48 hours, then fixed in position with a clear preservative film, wetted with 70% ethanol, then scanned in a Micro-CT scanning tube, and quantitatively analyzed using analytical software and a three-dimensional reconstruction platform. Wherein the detection area is calcified meniscus and synovial tissue, namely osteophyte, and the detection parameter is the volume of the calcified meniscus and synovial tissue.
Results: fig. 5 shows 3D reconstructed images of knee Micro-CT, from left to right, sham+pbs, dmm+pbs, dmm+msab, respectively. Fig. 6 shows a knee joint osteophyte volume statistical plot, with the osteophyte volume on the ordinate and the group on the abscissa, in order of sham+pbs, dmm+pbs, dmm+msab.
As can be seen, the dmm+pbs treated mice showed a significant increase in knee joint osteophyte formation compared to sham+pbs treated mice, indicating that medial meniscus modeling changes the mouse knee joint microstructure, and abnormal bone remodeling occurred, resulting in instability of the knee joint.
Compared with the DMM+PBS treatment group, the DMM+MSAB treatment group injects MSAB into the joint cavity of the mouse, so that the generation of osteophytes is effectively reduced, and the MSAB can effectively relieve the bone destruction and absorption and reduce abnormal bone remodeling, thereby playing a role in protecting the bone structure of the knee joint.
Example 4: histological examination of the effect of MSAB on cartilage structural damage
The right knee joint tissues of the three groups of mice obtained in step (1) in example 3 were fixed in 4% paraformaldehyde solution for 3 days, then decalcified in formic acid solution for 1 week, after which the solution was changed every 3 days, dehydrated with gradient ethanol and paraffin-embedded, cut into thick sagittal sections of 5 μm, stained with safranin O-fast green and observed for changes in tissue morphology under normal light microscope to evaluate cartilage degeneration of the knee joints of the mice.
Results: fig. 7 shows safranin O-fast green stained images of the right knee joint of mice, from left to right, sham+pbs, dmm+pbs, dmm+msab, respectively.
It was found that the tibial cartilage surface of the Sham + PBS treated group was bright and intact, whereas the cartilage surface of the DMM + PBS treated group was almost lost and revealed bone tissue underlying the cartilage, a large amount of matrix was lost, the number of chondrocytes was also reduced, indicating that medial meniscus destabilization in mice resulted in joint destruction and serious deformity.
Compared with the DMM+PBS treatment group, the articular cartilage surface of the DMM+MSAB treatment group has fewer defect focuses and retains most cartilage tissues, and the cartilage surface of the tibial plateau is continuous, which shows that the injection of MSAB into an osteoarthritis mouse can remarkably inhibit the loss of matrix, improve the coloring of cartilage layers, reduce the hypertrophy and apoptosis of cartilage cells and relieve the symptoms of cartilage structure injury.
Example 5: degenerative change scoring of MSAB effect on cartilage structural damage
Three sets of sections obtained in example 4 were scored for degenerative changes by different researchers, including cartilage area, cartilage degeneration score, synovitis score, osteophyte score. The cartilage degeneration scoring standard refers to cartilage International osteoarthritis research institute (OsteoarthritisResearchSociety International, OARSI) score. Synovitis scores were obtained from the sum of scores of the degree of synovial lining cell proliferation, villus proliferation and perivascular lymphocyte and monocyte infiltration to assess pathological changes in the synovium. Among these, the synovial lining cell proliferation scoring criteria were 1-2 layers of cytometer 0 score, 3-5 layers of cytometer 2 score, 6 layers and above 2 score; the villus proliferation scoring standard is 0 score of absence, 1 score of less, scattered and short, 2 scores of finger-shaped projection and 3 scores of finger-shaped projection and diffuse reflection; the degree scoring standard for perivascular lymphocytes and mononuclear cell infiltration was normally scored at 0 score, and the apparent cell infiltration was scored at 5 score in combination with the lymphoid follicle. The osteophyte score includes the size and maturity of the osteophyte, wherein the size of the osteophyte is rated as 4: grade 0 normal, grade 1 slightly increased, grade 2 moderately increased, grade 3 significantly increased; the maturity of osteophytes is classified as 4 grades: level 0 normal, level 1 significant cartilage ossification, a mix of level 3 bone and cartilage, level 4 significant ossification.
Results: fig. 8 shows the results of degenerative change scoring, wherein fig. 8A-8E represent OARSI score, tibial cartilage area scale, synovitis score, osteophyte size score, osteophyte maturity score, and on the abscissa, the sham+pbs, dmm+pbs, dmm+msab treatment groups, respectively, from left to right.
It can be seen that the OARSI score was significantly increased in the dmm+pbs treated mice compared to the sham+pbs treated mice, while the tibial cartilage area was severely reduced, indicating that the extent of articular cartilage damage at the femur and tibia was increased, abrasion occurred, and cartilage was thinned, indicating that osteoarthritis developed. In addition, the synovitis score of the dmm+pbs treated group increased significantly, indicating that the joint capsule of the group of mice was impacted, causing inflammation of the synovium, indirectly reflecting the development of osteoarthritis. In addition, the osteophyte size score and the osteophyte maturity score of the DMM+PBS treatment group are obviously increased, which indicates that biomechanics in joint cavities of the mice in the group are unstable, the supporting direction is changed, synovial tissues are stimulated to generate the osteophytes, and meanwhile, cartilage is calcified and has high maturity. Taken together, each index directly or indirectly demonstrated that the dmm+pbs treated group successfully constructed a mice model of osteoarthritis for medial meniscal instability.
Compared with the mice in the DMM+PBS treatment group, the OARSI score, the synovitis score, the osteophyte size score and the osteophyte maturity score of the mice in the DMM+MSAB treatment group treated by injecting MSAB into the joint cavity are obviously reduced, the articular cartilage area is obviously increased, and the MSAB can effectively relieve cartilage injury in the osteoarthritis process, so that the aim of preventing or treating is fulfilled.
In summary, the application provides an application of a matrix metalloproteinase inhibitor in preparing a medicine for preventing or treating osteoarthritis cartilage injury. In particular, MSAB is adopted to inhibit the expression of matrix metalloproteinase in chondrocytes, so that the damage of cartilage structure in the course of osteoarthritis is improved, and an important reference is provided for guiding treatment of osteoarthritis.
The foregoing are merely some embodiments of the application. It will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the spirit of the application.
Claims (5)
1. Use of a matrix metalloproteinase inhibitor in the manufacture of a medicament for the prevention or treatment of cartilage damage in osteoarthritis, wherein the matrix metalloproteinase inhibitor is methyl3- { [ (4-methylphenyl) sulfonyl ] amino } benzoate or a pharmaceutically acceptable salt thereof.
2. Use of a matrix metalloproteinase inhibitor according to claim 1 for the manufacture of a medicament for the prevention or treatment of cartilage damage due to osteoarthritis, wherein the matrix metalloproteinase inhibitor effects the prevention or treatment of cartilage damage due to osteoarthritis by inhibiting the expression of matrix metalloproteinases mmap 3, mmap 13, adams 4 and/or adams 5.
3. Use of a matrix metalloproteinase inhibitor according to claim 2 for the preparation of a medicament for the prevention or treatment of cartilage damage due to osteoarthritis, wherein the matrix metalloproteinase inhibitor effects inhibition of expression of matrix metalloproteinases mmap 3, mmap 13, adams 4 and/or adams 5 by inhibiting activation of WNT/β -catenin signaling pathway.
4. Use of a matrix metalloproteinase inhibitor according to claim 1 for the manufacture of a medicament for the prevention or treatment of cartilage damage in osteoarthritis by inhibiting calcification of meniscus and/or neogenesis of synovial tissue.
5. Use of a matrix metalloproteinase inhibitor according to any of claims 1-4, in the preparation of a medicament for the prevention or treatment of cartilage damage due to osteoarthritis, wherein the effective concentration of matrix metalloproteinase inhibitor is 15mg/kg body weight.
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