Increased HIF-1α in Knee Osteoarthritis Aggravate Synovial Fibrosis via Fibroblast-Like Synoviocyte Pyroptosis

Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. Our last report showed that NLRP1 and NLRP3 inflammasomes may mediate LPS/ATP-induced FLSs pyroptosis in KOA. In the present study, we found an elevated hypoxia-inducible factor-1 alpha (HIF-1 alpha) level in the synovial tissue of KOA model rats, and inhibiting the increase of HIF-1 alpha could improve synovial fibrosis in rats. Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. FLSs transfected with siRNA HIF-1 alpha showed a reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins was also downregulated. Additionally, FLSs transfected with or without siRNA GSDMD were exposed to hypoxia. GSDMD silencing can significantly reduce both gene and protein levels of fibrogenic markers transforming growth factor-beta (TGF-beta), procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2), collagen type I alpha 1 chain (COL1A1), and tissue inhibitor of metalloproteinases 1 (TIMP1). Taken together, our findings indicate that increased HIF-1 alpha is highly involved in the KOA synovial fibrosis. Moreover, elevated HIF-1 alpha may aggravate synovial fibrosis via FLS pyroptosis.