The Role And Mechanism Of MiR-146b ?2Macroglobulin Signal Axis In The Pathogenesis Of OA

ObjectiveOsteoarthritis(OA)is the most common degenerative joint disease in the aging population.Because of the absence of nerves and blood vessels in the cartilage tissue,it is extremely difficult to be diagnosed at the early stage of the disease,and those with symptoms are already in the middle and late stages of the disease.It is one of several diseases with a high disability rate.The irreversible damage and degradation of cartilage tissue is the most important pathological feature of OA,and how to prevent or delay the damage of cartilage tissue has been focused in the field.Normal cartilage tissue consists of articular cartilage and cartilage extracellular matrix,of which the extracellular matrix accounts for most of the dry weight,and its normal metabolism is essential to maintain the physiological function of articular cartilage.It is not known whether macroglobulin ?2M,a broad-spectrum protease inhibitor,plays a regulatory role in this process.In this study,we will investigate the role and potential mechanisms of macroglobulin ?2M in OA pathology through clinical specimens,experimental animal models,and chondrocyte models.MethodThe expression of macroglobulin ?2M was detected by pathological assessment of clinical OA patients and normal articular cartilage specimens;the expression of macroglobulin ?2M in age-related cartilage injury was detected by collecting articular cartilage specimens from mice at 6M,12M,18M,and 24M ages;the expression of macroglobulin ?2M in traumatic by constructing a mouse knee instability DMM-OA model.To observe the effect of exogenous supplementation of macroglobulin ?2M on the pathological process of OA by constructing a macroglobulin ?2M lentivirus and performing knee joint cavity injection in OA mice.Through target gene prediction,screen upstream microRNA and detect its interaction relationship in OA.ResultsThe expression of macroglobulin ?2M was down-regulated in human-derived specimens of OA patients,and by constructing DMM-OA model mice,the assay results showed that the expression of macroglobulin ?2M showed fluctuating changes,and the expression was up-regulated in the initial stage of disease development,however,the expression gradually decreased with the further development of the disease,and similar results were obtained in cartilage tissues of mice at different ages,and the macroglobulin ?2M low basal expression,increased secretion at the beginning of cartilage injury,and significantly decreased secretion at the later stages.Exogenous macroglobulin ?2M lentiviral treatment was effective in reducing and improving articular cartilage wear,preventing proteoglycan loss and extracellular matrix degradation,helping to maintain cartilage extracellular matrix metabolic homeostasis,and reducing the OARSI score of osteoarthritis in mice,suggesting that it could delay the pathological process in OA mice.Macroglobulin ?2M is the direct target of miR-146b.miR-146b negatively regulates the proliferation and apoptosis of chondrocytes and the dynamic balance of extracellular matrix,and this effect is achieved through the PI3K/AKT pathway.In vivo experiments showed that miR-146b inhibition was effective in delaying OA pathological changes.ConclusionThe expression of macroglobulin ?2M in osteoarthritis showed fluctuating changes,increasing at the beginning and then decreasing,and exogenous supplementation of macroglobulin ?2M could effectively delay the process of osteoarthritis in mice.miR-146b could negatively regulate the biological function of macroglobulin ?2M,and miR-146b inhibition could help maintain the positive stabilizing effect of chondrocyte activity and extracellular matrix metabolism.