WISP-3 promotes PDGF-B-mediated angiogenesis through suppression of let-7b-5p in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation accompanied by pathological angiogenesis, which contributes to pannus formation and disease progression. However, the upstream mechanisms regulating pathological angiogenesis in RA remain incompletely understood. In this study, bioinformatic analysis of two independent Gene Expression Omnibus (GEO) datasets, immunohistochemical analysis of human synovial tissues, and functional studies using MH7A synovial fibroblasts and HUVEC tube formation assays were performed to investigate the role of WNT1-inducible signaling pathway protein 3 (WISP-3) in RA angiogenesis. WISP-3 expression was consistently elevated in RA synovial tissues compared with healthy controls. Recombinant WISP-3 significantly enhanced endothelial tube formation and increased platelet-derived growth factor-B (PDGF-B) expression in MH7A cells. Mechanistically, WISP-3 activated the PI3K/p85/Akt/mTOR signaling pathway, whereas pharmacological inhibition or siRNA-mediated knockdown of p85, Akt, or mTOR markedly attenuated PDGF-B expression and angiogenic activity. WISP-3 also suppressed hsa-let-7b-5p expression, and restoration of hsa-let-7b-5p using a synthetic mimic significantly reduced WISP-3-induced PDGF-B expression and endothelial tube formation. Luciferase reporter assays further confirmed PDGF-B as a direct target of hsa-let-7b-5p. These findings identify a previously unrecognized WISP-3/p85/Akt/mTOR/hsa-let-7b-5p/PDGF-B signaling axis that promotes pathological angiogenesis and provides new mechanistic insight into synovial vascular remodeling in RA.