The JAK inhibitor Tofacitinib inhibits structural damage in osteoarthritis by modulating JAK1/TNF-alpha/IL-6 signaling through Mir-149-5p

Background: Osteoarthritis (OA), a common articular bone degenerative disease, is exacerbated by proinflammatory cytokine signaling. Mounting evidence suggests that epigenetic modifiers, namely microRNAs (miRs), are dysregulated in articular chondrocytes (ACs) during OA.& nbsp; Methods: An initial database search led to the identification of miR-149-5p, which was downregulated in clinical OA samples and contributed to chronic inflammation, by increasing TNF-alpha/IL-6 signaling within the synovium, and OA progression.& nbsp; Results: We overexpressed miR-149-5p in the human chondrocyte cell lines C20A4 and C28/I2 to examine its role in chondrocyte hypertrophy and osteoclastogenesis and found a significant decrease in IL-6 expression, an increase in SOX9 expression, and a reduction in chondrocyte hypertrophy. We evaluated the therapeutic effects of tofacitinib (JAK inhibitor) by suppressing inflammation and restoring miR-149-5p expression. Tofacitinib-treated C20A4 and C28/I2 cells had a significantly lower expression of JAK/IL-6/TNF-alpha and an increased level of miR149-5p. Notably, tofacitinib treatment reduced AC hypertrophy and secretion of RANKL and IL-6. Finally, an OA mouse model was used to evaluate the therapeutic potential of tofacitinib. Intra-articular injection of tofacitinib significantly lowered arthritis scores and bone degradation in treated mice compared with their control counterparts.& nbsp; Conclusion: We show for the first time that tofacitinib suppresses the expression level of JAK1/TNF-alpha/IL-6 by upregulating miR-149-5p level. Our findings revealed the functional association between proinflammatory JAK1/TNF-alpha/IL-6 signaling and ACs development and highlight the therapeutic potential of tofacitinib in OA.

Automated summary

Research has revealed that miR-149-5p is downregulated in clinical OA samples, contributing to chronic inflammation by increasing TNF-alpha/IL-6 signaling within the synovium and OA progression. Additionally, therapeutic effects of tofacitinib, a JAK inhibitor, were evaluated in in vitro and in vivo OA models, showing potential in suppressing inflammation and restoring miR-149-5p expression.