JAK inhibitors alleviate metabolic dysregulation, inflammation and fibrosis in osteoarthritis: insights from human joint cells and synovium.

Abstract

Objectives: Osteoarthritis (OA) presents a significant clinical challenge due to its heterogeneous nature, characterized by cartilage degradation, inflammation, and fibrosis. Current treatments offer limited efficacy, highlighting the need for novel therapeutic approaches. Our study aimed to investigate the effects of two JAK inhibitors, tofacitinib and baricitinib, on various hallmarks of OA in human joint cells and synovium.

Methods: Human OA fibroblast-like synoviocytes (FLS), OA chondrocytes, and synovial explants were cultured with tofacitinib or baricitinib, with or without additional stimulation (IL-1β or TGF-β). The levels of p-STAT1, p-STAT3, SOX9, and α-SMA were assessed by Western blot whereas SOX9, COL2A1, ACAN, ACTA2, CTGF and COL3A1 gene expression was examined by RT-qPCR. Secreted IL-6, MMP-1, MMP-3, MMP-13 were measured in supernatants by ELISA.

Results: Tofacitinib or baricitinib increased the expression of anabolic factors SOX9, COL2A1, and ACAN while decreasing MMP-13 and MMP-3 levels in OA chondrocytes. Secreted levels of IL-6 and MMP-1 were significantly reduced in IL-1β-stimulated OA FLS and in OA synovial explants treated with tofacitinib or baricitinib. Finally, baricitinib decreased some fibrotic markers: α-SMA expression, ACTA2 gene expression, and CTGF levels in TGF-β-stimulated OA FLS.

Conclusion: Tofacitinib and baricitinib modulate some features of OA pathophysiology by promoting anabolic processes in OA cartilage, reducing inflammation in OA synovium, and attenuating some fibrotic factors in OA FLS. These findings demonstrate the potential use of tofacitinib and baricitinib as therapeutic options for managing OA, and highlight pathogenic pathways to target for further research and development of new OA treatment strategies.