| Objective: Osteoarthritis(OA),a common degenerative disease affecting articular cartilage,is caused by multiple factors and currently there are few approaches to effectively delay its progression.This study aimed to evaluate whether Kartogenin(KGN),Strontium gluconate(Glu-Sr)and Aspirin(As)could reduce OA pathology severity in osteoarthritic cartilage by targeting chondrogenic endogenous repair.Methods: In order to evaluate the ability of KGN,Glu-Sr and Aspirin to aid in repair of cartilage in OA in vivo,its effects on a destabilization of the medial meniscus model(DMM)of OA was tested.The degree of articular cartilage degeneration was evaluated histologically by,toluidine blue staining,safranin O and fast green staining,and IHC staining of collagen II.Furthermore,the chondrogenic differentiation ability of the three drugs to mesenchymal stem cells(MSCs)/ cartilage-derived stem/progenitor cells(CSPCs)was examined.RNA sequencing was used to investigate the preliminary mechanism of Glu-Sr repair of OA cartilage degeneration.RESULTS: Oral administration of KGN(5mg/kg)could effectively reduce DMM cartilage degeneration in STR/Ort mice.The KGN decomposition product 4-aminobiphenyl(4-ABP)was found to be involved in the repair of cartilage by HPLC-MS.It was showed that 4-ABP could promote chondrogenic differentiation of MSCs/CSPCs regardless of chondrogenic induction.In addition,4-ABP was also detected in the cartilage after intraarticular injection of KGN.Animal experiments further showed that intra-articular injection of 4-ABP can effectively repair DMM cartilage degeneration.These results indicate that KGN affects the chondrogenic differentiation of MSCs/CSPCs and reduces DMM cartilage degeneration through its decomposition product 4-ABP.Oral administration of Glu-Sr(1350mg/kg)could significantly reduce DMM cartilage degeneration in DMM rats,and decreased the expression of inflammatory factors and up regulated the expression of Collagen II,Aggrecan and Sox9 in chondrocytes of DMM rats.Further experiments showed that Glu-Sr treatment could reduce IL-1β mediated chondrocyte inflammation and promoted chondrogenic genes expression.In addition,Glu-Sr could promote chondrogenic differentiation of bone marrow mesenchymal stem cells.RNA sequencing results indicated that Glu-Sr effects on chondrogenic differentiation through regulating the expression of ACTG1,CTGF and FGF1 in the Hippo pathway.These results indicated that Glu-Sr could effectively reduce OA cartilage degeneration by promoting chondrogenic differentiation of bone marrow mesenchymal stem cells.In vitro experiments showed that low concentration of As could promote the proliferation and chondrogenic differentiation of CSPCs.Histopathological results confirmed that both intra-articular injection and oral administration of As could reduce DMM cartilage degeneration.Meanwhile,oral administration of As could effectively prevent cartilage degeneration of spontaneous osteoarthritis in STR/Ort mice.These results indicated that As may be used for the treatment and prevention of OA.Conclusion: KGN,Glu-Sr and As treatment effectively reduces articular cartilage degeneration through actived endogenous repair of cartilage,such as promote the chondrogenic differentiation of MSCs/CSPCs. |
