Scholarlink

Background <p>Fibroblast-like synoviocytes (FLS) are central mediators of synovial inflammation and joint destruction in rheumatoid arthritis (RA). While tumor necrosis factor-α (TNFα) 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.</p> Methods <p>LIN28A–let-7b regulation and functional consequences were investigated in TNFα-stimulated MH7A synoviocytes and primary murine FLS. Pathway inhibitor experiments were performed using p38 and NF-κB 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.</p> Results <p>TNFα 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-κB signaling pathways. Inhibition of p38 or NF-κB 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.</p> Conclusion <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月13日

查看全文
  • Hee Young Chae,
  • Kyungrim Yi,
  • Su-Geun Lim,
  • Ji Yeong Park,
  • Hyejin Hyung,
  • Si-Yong Kim,
  • Wanil Kim,
  • Sang-Il Lee,
  • Dong Kyu Choi,
  • Myoung Ok Kim,
  • Zae Young Ryoo,
  • Jiwon Ko,
  • Soyeon Jang

摘要

Background

Fibroblast-like synoviocytes (FLS) are central mediators of synovial inflammation and joint destruction in rheumatoid arthritis (RA). While tumor necrosis factor-α (TNFα) 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 TNFα-stimulated MH7A synoviocytes and primary murine FLS. Pathway inhibitor experiments were performed using p38 and NF-κB 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

TNFα 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-κB signaling pathways. Inhibition of p38 or NF-κB 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.