Effects And Mechanism Of Chondrocyte Metabolism In Osteoarthritis Pathogenesis

Cartilage homeostasis is maintained by chondrocytes,the unique resident cells that synthesize cartilage-specific extracellular matrix(ECM),catabolic and anabolic factors.The balance between anabolic and catabolic factors is disturbed in osteoarthritis,contributing to chronic cartilage destruction.Here,we investigated the roles of Interleukin-17A and Kdm6b in chondrocytes catabolic/anabolic metabolism and osteoarthritis pathogenesis.Pro-inflammatory cytokines are responsible for disruption of the cartilage homeostasis and initiation of the catabolic pathway.However,the pathogenic mechanism of each pro-inflammatory cytokine need to be elucidated in more detail.We find a subpopulation of OA patient with elevated IL-17A expression level in synovium.Subsequent analysis demonstrated that higher level of IL-17A in the knee joints was correlated with accelerated OA progress.16S rRNA sequencing analysis revealed that Segmented filamentous bacteria(SFB)residing in gut was positively correlated with IL-17A level and cartilage destruction.Deletion of SFB with antibiotic vancomycin attenuated osteoarthritis progress in DMM operated mice and this alleviation was reversed after microbiota reconstitution.Further experiments showed that the administration of IL-17A accelerated articular cartilage degradation through enhancing activities of HIF-2a and its target MMP13,as well as inhibiting matrix synthesis of chondrocytes in vitro and in vivo.Finally,we performed DMM surgery in MINK1-/-mice which presented a high IL-17A level and observed similar results.Previous researches illustrated that epigenetic regulation in response to various stimulus has important impacts on joint cartilage development and homeostasis.However,the roles of particular histone demethylases on cartilage tissue have not been uncovered.In the following part,we investigated whether Kdm6b can be manipulated to promote anabolic metabolism of chondrocytes for osteoarthritis treatment.We find that Kdm6b expression was significantly increased during cartilage development.Col2al-CreERT2;Kdm6b/f/mice displayed obvious inhibited ECM synthesis,decreased chondrocytes proliferation and skeletal abnormalities at E16.5 and E18.5 with intraperitoneal injection of Tamoxifen at E12.5.RNA-Seq and qRT-PCR analysis revealed decreased expression of chondrocyte anabolic genes,Col2al and Acan,in Col2al-CreERT2;Kdm6bf/f chondrocytes.Furthermore,Col2a1-CreERT2;Kdm6bf/f mice exhibited accelerated OA development at 8 and 12 weeks following surgical induction.Decreased expression of Kdm6b was also observed in both mice and human OA cartilage samples.These findings revealed that IL17A and Kdm6b play important roles in maintaining cartilage homestasis during OA progression via metabolic modulation of chondrocytes.Understanding the role of gut microbiota,pro-inflammatory cytokines and epigenetic mechanism in the maintainace of joint cartilage homeostasis would be useful to develop new therapeutic modalities for OA.