LIN28A-let-7b axis drives the aggressive and proinflammatory phenotype of rheumatoid arthritis fibroblast-like synoviocytes

초록

Background Fibroblast-like synoviocytes (FLS) are central mediators of synovial inflammation and joint destruction in rheumatoid arthritis (RA). While tumor necrosis factor-alpha (TNF alpha) is known to activate FLS, the upstream regulators that connect inflammatory stimulation with sustained stromal pathogenicity remain poorly defined. The LIN28A-let-7 microRNA axis regulates proliferation and invasiveness in diverse pathological contexts, but its role in RA FLS remains unclear. Methods LIN28A-let-7b regulation and functional consequences were investigated in TNF alpha-stimulated MH7A synoviocytes and primary murine FLS. Pathway inhibitor experiments were performed using p38 and NF-kappa B inhibitors, and pharmacologic modulation of the LIN28-let-7 interaction was evaluated using the small-molecule inhibitor C1632. Expression of LIN28A and let-7b was also examined in synovial tissues from collagen-induced arthritis (CIA) mice. Results TNF alpha stimulation induced reciprocal regulation of LIN28A and let-7b, with increased LIN28A expression and reduced let-7b levels in MH7A cells and CIA synovial tissues. LIN28A overexpression enhanced proliferation, migration, invasion, and inflammatory mediator production, and increased expression of the let-7 target HMGA2 and matrix-remodeling enzymes. These changes were accompanied by activation of MAPK and NF-kappa B signaling pathways. Inhibition of p38 or NF-kappa B attenuated LIN28A-associated inflammatory gene expression. Primary fibroblast-like synoviocytes isolated from Lin28a transgenic mice recapitulated these phenotypes. In addition, disruption of the LIN28-let-7 interaction using C1632 partially restored let-7b expression and suppressed migration, invasion, inflammatory gene expression, and signaling activation. Conclusion LIN28A may act as an upstream regulator of synoviocyte pathogenicity in RA. Targeting the LIN28A-let-7b axis may represent a therapeutic strategy to modulate stromal contributions to disease progression.

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