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Background <p>Osteoarthritis (OA) involves progressive extracellular matrix (ECM) degradation in articular cartilage. We previously revealed that the m<sup>6</sup>A demethylase ALKBH5 stabilizes <i>Runx2</i> mRNA in chondrocytes via YTHDF1, thereby increasing <i>MMP</i> and <i>ADAMTS</i> expression, causing ECM degradation. However, the transcriptional co-regulators of Runx2 remain unidentified.</p> Methods <p>OA was induced in mice via injection of sodium monoiodoacetate (MIA). The histological architecture and proteoglycan content of the articular cartilage were evaluated using H&amp;E and Safranin O-Fast Green staining, while subchondral bone microarchitecture was assessed by micro-computed tomography. Circulating proinflammatory cytokine levels were determined by ELISA.</p> Results <p>Immunoprecipitation and mass spectrometry analyses of articular cartilage from MIA-induced OA mice identified the transcriptional coactivator EYA1 (Eyes Absent Homolog 1) and CIITA (Class II Major Histocompatibility Complex Transactivator) as novel Runx2-interacting proteins. In vitro and in vivo experiments demonstrated that EYA1, CIITA, and Runx2 form a functional EYA1–CIITA–Runx2 complex that binds to the promoters of <i>MMP</i> and <i>ADAMTS</i> genes and activates their expression. Silencing any member of the complex significantly reduced transcription of these matrix-degrading enzymes. Furthermore, we identified EYA1 as a phosphatase that dephosphorylates CIITA at serine 782, a phosphorylation site targeted by Pim3 (provirus integration site for Moloney murine leukemia virus 3) under inflammatory conditions.</p> Conclusion <p>Our findings uncover a previously unrecognized transcriptional mechanism in OA pathogenesis, in which EYA1 promotes ECM degradation by regulating CIITA dephosphorylation and assembling a transcriptional complex with CIITA and Runx2. Targeting this pathway may provide a promising therapeutic strategy for OA.</p>

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EYA1 regulates CIITA phosphorylation to promote EYA1–CIITA–Runx2 complex formation and extracellular matrix integrity in osteoarthritis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • Guanghua Nie,
  • Yi Li,
  • Hongmou Zhao,
  • Dong Wang,
  • Yan Zhang,
  • Xinquan Yang,
  • Xiaodong Wen

摘要

Background

Osteoarthritis (OA) involves progressive extracellular matrix (ECM) degradation in articular cartilage. We previously revealed that the m6A demethylase ALKBH5 stabilizes Runx2 mRNA in chondrocytes via YTHDF1, thereby increasing MMP and ADAMTS expression, causing ECM degradation. However, the transcriptional co-regulators of Runx2 remain unidentified.

Methods

OA was induced in mice via injection of sodium monoiodoacetate (MIA). The histological architecture and proteoglycan content of the articular cartilage were evaluated using H&E and Safranin O-Fast Green staining, while subchondral bone microarchitecture was assessed by micro-computed tomography. Circulating proinflammatory cytokine levels were determined by ELISA.

Results

Immunoprecipitation and mass spectrometry analyses of articular cartilage from MIA-induced OA mice identified the transcriptional coactivator EYA1 (Eyes Absent Homolog 1) and CIITA (Class II Major Histocompatibility Complex Transactivator) as novel Runx2-interacting proteins. In vitro and in vivo experiments demonstrated that EYA1, CIITA, and Runx2 form a functional EYA1–CIITA–Runx2 complex that binds to the promoters of MMP and ADAMTS genes and activates their expression. Silencing any member of the complex significantly reduced transcription of these matrix-degrading enzymes. Furthermore, we identified EYA1 as a phosphatase that dephosphorylates CIITA at serine 782, a phosphorylation site targeted by Pim3 (provirus integration site for Moloney murine leukemia virus 3) under inflammatory conditions.

Conclusion

Our findings uncover a previously unrecognized transcriptional mechanism in OA pathogenesis, in which EYA1 promotes ECM degradation by regulating CIITA dephosphorylation and assembling a transcriptional complex with CIITA and Runx2. Targeting this pathway may provide a promising therapeutic strategy for OA.