TCF12 Activates The TGF-β Signaling Pathway To Promote Osteoarthritis

BackgroundOsteoarthritis(OA)is a highly prevalent joint disease in the elderly,which is pathologically characterized by degeneration of articular cartilage,synovitis,sclerosis of subchondral bone,and osteophyte generation.The pathogenesis of osteoarthritis is complex,and it is considered to be associated with multiple risk factors,including genetic factors,constitutional factors(such as age,gender,obesity,gender,and high bone mineral density),and multiple aspects such as biochemistry and biomechanics.However,the specific mechanism remains to be elucidated.At present,there is no effective treatment to improve the disease in osteoarthritis,and joint replacement is used as the final treatment option.Previous studies have shown that TCF12 plays an important role in regulating osteogenic differentiation and tumor metastasis,but the mechanism of TCF12 in osteoarthritis has not yet been reported.ObjectiveIn this study,we intend to clarify the expression of TCF12 in osteoarthritis,verify the regulatory role of TCF12 in osteoarthritis,and finally clarify the upstream and downstream mechanisms of regulating TCF12.Method1.To collect the tibial plateau of patients with osteoarthritis after knee replacement surgery,the medial side with severe injury as the experimental group,the lateral side with mild injury as the control group,and detected the expression of TCF12 after pathological evaluation of cartilage samples;2.DMM-OA model was performed in 10-week mice,and samples were collected at 4 and 8 weeks to detect the expression of TCF12 in arthritic cartilage;3.Construct TCF12 lentiviral vector,lentiviral injection was performed in the knee joint cavity of DMM mice,and sections were taken for safranin O-fast green staining and HE staining to determine the degree of cartilage destruction.To observe the effect of intervening TCF 12 expression on the pathological process of OA;4.The TCF 12 promoter was screened by bioinformatics target gene prediction,and its interaction in OA was detected.Results1.The results showed that the expression of TCF 12 was up-regulated in human osteoarthritis OA cartilage,significantly up-regulated in DMM-OA mouse model specimens,and up-regulated in IL-1β-induced cell models and explants.2.Intra-articular injection of TCF 12 interfered with lentivirus to down-regulated the expression of TCF 12 in MM-OA model mice,which alleviated cartilage destruction,proteoglycan loss,degradation of extracellular chondrocyte and chondrocyte senescence,and contributed to maintaining the metabolic balance of extracellular chondrocyte.The OARSI score of osteoarthritis in mice was decreased and the pathological process of OA mice was delayed.3.It proved that TCF 12 directly targeted CXCR4,and TCF 12 could positively regulate CXCR4 involved in regulating the metabolism of cartilage extracellular matrix and chondrocyte senescence,and this effect was achieved through the TGF-β/smad2 signaling pathway.ConclusionThe expression of TCF12 is up-regulated in osteoarthritis,exogenous supplementation of TCF12 can effectively delay the process of osteoarthritis in mice.Moreover,TCF12 can positively regulate CXCR4 to produce biological functions,and the inhibition of TCF12 helps to maintain the balance of extracellular matrix metabolism as well as chondrocyte senescence.