JAK Inhibitor Tofacitinib Ameliorates Inflammation Response and Osteogenic Differentiation in Immune-Mediated Inflammatory Arthritis in Rats.

OBJECTIVE

This study sought to investigate the mechanism by which tofacitinib affects inflammatory response and osteogenic differentiation in immune-mediated inflammatory arthritis in rats in relation to Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3).

METHODS

Wistar male rats were induced by the combination of bovine proteoglycan and incomplete/complete Freund's adjuvant to establish the immune-mediated inflammatory arthritis model. The clinical manifestations were observed. Hematoxylin and eosin staining was used to evaluate pathological changes in sacroiliac joints and surrounding cartilage. Additionally, the levels of osteogenic differentiation-related proteins, serum inflammatory factors, and alkaline phosphatase (ALP) were measured. Flow cytometry was conducted to analyze the proportion of Th17 cells in peripheral blood. Alizarin red staining detected the osteogenic differentiation of ligament fibroblasts.

RESULTS

The rats exhibited joint swelling, inflammatory infiltration in the sacroiliac joint, and cartilage destruction after modeling. Elevations were also detected in the levels of serum pro-inflammatory factors, the proportion of Th17 cells, ALP activity, phosphorylated (p)-JAK1/2, p-STAT3, osteogenic differentiation markers in ligament fibroblasts, as well as in the mineralized nodules. Tofacitinib intervention inhibited the phosphorylation of JAK and STAT3, downregulated bone differentiation-related proteins, decreased the mineralized nodules, reduced the activity of ALP, and decreased the levels of pro-inflammatory factors. However, the combined use of the STAT3 agonist Colivelin partially reversed the inhibitory effect of tofacitinib on joint inflammation and osteogenic differentiation.

CONCLUSION

Tofacitinib alleviated the inflammatory response in immune-mediated inflammatory arthritis and inhibited osteogenic differentiation in rats via inhibition of the JAK/STAT3 signaling pathway.