Periostin drives rheumatoid arthritis progression by regulating integrin αvβ3-mediated transforming growth factor-β1/SMAD signaling.

Periostin (POSTN), a non-structural extracellular matrix protein, plays a critical role in promoting tumor cell invasion, metastasis, and disease progression. We previously reported that POSTN mRNA and protein levels are markedly upregulated in the synovium of patients with rheumatoid arthritis (RA); however, its specific functions and underlying mechanisms remain unclear. In this study, we investigated the roles of POSTN in fibroblast-like synoviocytes (FLSs) and collagen-induced arthritis (CIA) model mice. POSTN mRNA and protein levels were markedly upregulated in primary RA-FLSs and closely associated with synovial fibrosis and angiogenesis. POSTN knockdown markedly reduced the cellular invasion, profibrotic phenotype, and vascular endothelial growth factor A secretion in RA-FLSs, whereas its overexpression exerted the opposite effects. Mechanistically, POSTN interacted with and regulated integrin αvβ3 (ITGαvβ3), leading to activation of the transforming growth factor (TGF)-β1/SMAD signaling pathway. Rescue experiments confirmed that POSTN played a critical role in promoting disease progression by regulating the ITGαvβ3/TGFβ1/SMAD axis. Moreover, adeno-associated virus 9-mediated POSTN knockdown alleviated joint destruction, synovial hyperplasia, fibrosis, and angiogenesis in CIA model mice. Collectively, our results suggest that POSTN drives RA progression by modulating the ITGαvβ3/TGFβ1/SMAD signaling pathway, highlighting its potential as a novel therapeutic target for RA.