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<p>Osteoarthritis (OA) is a chronic degenerative joint disease involving aberrant immune activation, cartilage degradation, and synovial inflammation. The Hedgehog (Hh) signaling pathway, which is largely quiescent in healthy adult articular cartilage, becomes aberrantly reactivated in OA. This reactivation has been associated with chondrocyte hypertrophy, extracellular matrix degradation, and increased production of pro-inflammatory cytokines such as IL-1β and TNF-α through crosstalk with inflammatory pathways including NF-κB and the NLRP3 inflammasome.</p><p>Pharmacological inhibition of Smoothened (Smo) with cyclopamine, a classical Hh antagonist, has been shown in preclinical models to suppress hypertrophic differentiation, reduce the expression of matrix-degrading enzymes (MMP-13, ADAMTS-5), and attenuate inflammatory mediator release, resulting in decreased cartilage damage and synovial inflammation. This review synthesizes current mechanistic evidence linking Hh signaling to OA-associated inflammation, evaluates cyclopamine-based studies as a proof-of-concept tool compound, and discusses key translational challenges along with future directions for the development of joint-targeted Hh pathway modulators.</p>

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Hedgehog signaling in osteoarthritis-associated inflammation: mechanistic insights and therapeutic potential of smoothened inhibition

  • 期刊论文

  • 发表日期：

    2026年6月19日

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  • Haiyang Kou,
  • Huaiquan Liu,
  • Lingyan Lai,
  • Shili Yang,
  • Xinyan Zhang,
  • Yunling Xu,
  • Yu Sun,
  • Bo Chen

摘要

Osteoarthritis (OA) is a chronic degenerative joint disease involving aberrant immune activation, cartilage degradation, and synovial inflammation. The Hedgehog (Hh) signaling pathway, which is largely quiescent in healthy adult articular cartilage, becomes aberrantly reactivated in OA. This reactivation has been associated with chondrocyte hypertrophy, extracellular matrix degradation, and increased production of pro-inflammatory cytokines such as IL-1β and TNF-α through crosstalk with inflammatory pathways including NF-κB and the NLRP3 inflammasome.

Pharmacological inhibition of Smoothened (Smo) with cyclopamine, a classical Hh antagonist, has been shown in preclinical models to suppress hypertrophic differentiation, reduce the expression of matrix-degrading enzymes (MMP-13, ADAMTS-5), and attenuate inflammatory mediator release, resulting in decreased cartilage damage and synovial inflammation. This review synthesizes current mechanistic evidence linking Hh signaling to OA-associated inflammation, evaluates cyclopamine-based studies as a proof-of-concept tool compound, and discusses key translational challenges along with future directions for the development of joint-targeted Hh pathway modulators.