The Effect of the JAK-inhibitor Tofacitinib on Chondrocyte Autophagy in Osteoarthritis

Abstract Osteoarthritis (OA) is a multifactorial disease of the whole joint that has a complex pathogenesis. There is currently no cure for OA. Tofacitinib is a broad JAK inhibitor that can have an anti-inflammatory effect. The objective of this study was to investigate the effect of tofacitinib on the cartilage extracellular matrix in OA and determine whether tofacitinib exerts a protective effect by inhibiting the JAK1/STAT3 signaling pathway and upregulating autophagy in chondrocytes. We established an vitro OA model by exposing SW1353 cells to interleukin-1β (IL-1β) and induced OA in rats using the modified Hulth method. We found that IL-1β promoted the expression of OA-related matrix metalloproteinases (MMP-3 and MMP-13), reduced the expression of collagen II, reduced the expression of beclin1 and LC3-II/I, and promoted the accumulation of p62 in SW1353 cells. Tofacitinib attenuated IL-1β-stimulated changes in MMPs and collagen II and restored chondrocyte autophagy. In IL-1β-stimulated SW1353 cells, the JAK1/STAT3 signaling pathway was activated. Tofacitinib inhibited the IL-1β-stimulated expression of p-JAK1 and p-STAT3 and prevented translocation of p-STAT3 to the nucleus. In the rat model of OA, tofacitinib reduced articular cartilage degeneration by delaying cartilage extracellular matrix degradation and increasing chondrocyte autophagy. Our study demonstrates that chondrocyte autophagy was impaired in experimental models of OA. Tofacitinib reduced the inflammatory response and restored the damaged autophagic flux in OA.