Inhibition of peritendinous adhesion through targeting JAK2-STAT3 signaling pathway: The therapeutic potential of AG490.

Peritendinous adhesion is a common complication following tendon injury repair, posing a significant clinical challenge that requires urgent attention. The primary cause of peritendinous adhesion is the excessive deposition of collagen matrix due to the abnormal proliferation of fibroblasts in an inflammatory state. Janus kinase2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) are key signaling molecules involved in cell proliferation and fibrosis development in various organs. However, the role of the JAK-2 and STAT3 signaling pathways in peritendinous adhesion fibrosis remains unclear. In our study, we first observed upregulation of p-JAK2 and p-STAT3 proteins in human peritendinous adhesion specimens and rat peritendinous adhesion models. In vitro, the JAK2/STAT3 pathway inhibitor AG490 effectively inhibited TGF-β1-induced fibroblast proliferation. Wound healing and transwell assays demonstrated that AG490 suppressed TGF-β1-induced fibroblast migration. Furthermore, we found that AG490 decreased the expression of pro-inflammatory factors, including IL-1β and TNF-α, as well as extracellular matrix (ECM) proteins in fibroblasts under TGF-β1 stimulation. In vivo, histological staining showed that AG490 prevented fibrous tissue formation in a rat model of tendon injury. Moreover, AG490 inhibited the overexpression of pro-inflammatory factors IL-1β and TNF-α, as well as ECM in the peritendinous adhesions. In conclusion, AG490 inhibited fibrosis and inflammation in injured tendons by targeting the JAK2-STAT3 signaling pathway, presenting a promising strategy for the prophylaxis of peritendinous adhesions.