Study On The Effect And Molecular Mechanism Of SM04690 In The Treatment Of Temporomandibular Joint Osteoarthritis

BackgroundTemporomandibular joint osteoarthritis(TMJOA)is a osteoarthropathy,which is characterized by progressive degeneration of articular cartilage and joint destruction.Currently,symptomatic treatment is a main method to treat TMJOA in clinic.In the advanced stage of the disease,even artificial joint replacement is required,and the overall therapeutic effect is still not ideal.Disease-modifying osteoarthritis drugs(DMOADs),as a hot research topic in the treatment of OA,the development of which in the field of temporomandibular joint osteoarthritis will be expected to improve the clinical problem of the lack of effective cure strategy for TMJOA.Wnt signaling pathway is involved in and regulates chondrocyte differentiation and cartilage metabolism.The steady-state balance mediated by Wnt signaling pathway is the basis for the normal differentiation of chondrocytes and cartilage function.Once the steady-state of Wnt signaling pathway is destroyed,the defects and excessive activation of β-catenin will elicit the cartilage matrix degradation.SM04690,as a small molecule inhibitor of Wnt signaling pathway is expected as DMOADs to be applied in the clinical treatment of OA.The research on SM04690 in the treatment of knee arthritis has completed phase I and phase II clinical trials.However,whether SM04690 has the same therapeutic effect on TMJOA remains to be further studied.This study explored the effect of Wnt signaling pathway inhibitor SM04690 on the progression of temporomandibular joint osteoarthritis and further studied the internal molecular mechanism by establishing in vivo TMJOA model and in vitro inflammatory model.The present study established the experimental foundation for SM04690 application in the field of TMJOA treatment.MethodsFirst,TMJOA models of rabbits and rats were established by the partial discectomy in the TMJ.The therapeutic effects of intra-articular injection of SM04690 on TMJOA were evaluated,the relative molecule expressions of which also were analyzed.Secondly,the in vitro studies utilized condylar chondrocytes isolated from TMJ.The intrinsic mechanism and downstream molecules of SM04690 on condylar chondrocytes were investigated by Polymerase Chain Reaction(PCR)and Westen Blot(WB).Finally,Fibrocartilage stem cells(FCSCs)were isolated in vitro and induced by SM04690 to evaluate the effect of SM04690 on the chondrogenic differentiation of FCSCs.ResultsIn this study,TMJOA models in rabbits and rats were successfully established by partial discectomy.Intra-articular injection of SM04690 can effectively reduce the OA pathological changes of condylar cartilage and subchondral bone,increase the expression of cartilage anabolic markers and reduce the expression of cartilage catabolic proteins.Secondly,the in vitro studies showed that SM04690 could effectively resist the promotion effect of TNF-α on Wnt signaling pathway.At the same time,SM04690 can effectively inhibit TNF-a-mediated down regulation of Col2a1,Aggrecan,SOX9,and up-regulation of MMP13,RUNX2.In addition,Wnt16 is a key factor in cartilage homeostasis,and its expression level is reduced under TNF-α induction,while SM04690 effectively reverses the inhibitory effect of TNF-αon Wnt16.Finally,SM04690 successfully induced the chondrogenic differentiation of FCSCs to form cartilage-like tissue.ConclusionsIntra-articular injection of SM04690 has a positive therapeutic effect on TMJOA induced by partial discectomy,which can effectively alleviate the cartilage degeneration and subchondral bone loss of TMJOA.The mechanism of SM04690-mediated chondrocyte/chondrocyte protection may be:SM04690 inhibits over-activated Wnt canonical signaling pathway in TMJOA by promoting Wnt16 expression,and ultimately reduces cartilage matrix degradation and promotes cartilage anabolism.In addition,SM04690 can effectively stimulate the chondrogenic differentiation potential of FCSCs,which suggests that SM04690 may promote cartilage regeneration.