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<p>Accumulating evidence has identified N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) regulation in the progression of age-related diseases. However, whether the m<sup>6</sup>A reader protein IGF2BP2 affects the occurrence of cartilage degeneration is still unknown. Western blotting revealed dose-dependent IGF2BP2 attenuation with increasing IL-1β concentrations in C28/I2 chondrocytes. Downregulation of IGF2BP2 caused impaired glycolysis and abnormal mitochondrial function, which ultimately resulted in senescence and disturbance of extracellular matrix homeostasis. Overexpressing HIF-1α at the cellular level in chondrocytes partially rescued mitochondrial dysfunction and senescence triggered by IGF2BP2 deficiency and thus alleviated the progression of cartilage degeneration. In vivo, chondrocyte-specific Igf2bp2-knockout mice (Col2a1-CreERT; Igf2bp2<sup>flox/flox</sup>) developed cartilage degeneration. Our study, for the first time, reveals the essential role of the m<sup>6</sup>A reader IGF2BP2 in the pathogenesis of cartilage degeneration through downregulation of HIF-1α and extends the potential role of the PINK1/Parkin pathway, downregulation of which leads to the onset of mitochondrial dysfunction and senescence in the progression of articular cartilage loss.</p>

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Deficiency of the m6A reader IGF2BP2 mediates cellular senescence of chondrocytes and triggers cartilage degeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Zhi-Han Shen,
  • Xu-Ran Li,
  • Jian Lu,
  • Po-Lin Liu,
  • Shu-Hang He,
  • Qing-Song Deng,
  • Ang Wang,
  • Ren Zhang,
  • Shi-Cong Tao,
  • Shang-Chun Guo

摘要

Accumulating evidence has identified N6-methyladenosine (m6A) regulation in the progression of age-related diseases. However, whether the m6A reader protein IGF2BP2 affects the occurrence of cartilage degeneration is still unknown. Western blotting revealed dose-dependent IGF2BP2 attenuation with increasing IL-1β concentrations in C28/I2 chondrocytes. Downregulation of IGF2BP2 caused impaired glycolysis and abnormal mitochondrial function, which ultimately resulted in senescence and disturbance of extracellular matrix homeostasis. Overexpressing HIF-1α at the cellular level in chondrocytes partially rescued mitochondrial dysfunction and senescence triggered by IGF2BP2 deficiency and thus alleviated the progression of cartilage degeneration. In vivo, chondrocyte-specific Igf2bp2-knockout mice (Col2a1-CreERT; Igf2bp2flox/flox) developed cartilage degeneration. Our study, for the first time, reveals the essential role of the m6A reader IGF2BP2 in the pathogenesis of cartilage degeneration through downregulation of HIF-1α and extends the potential role of the PINK1/Parkin pathway, downregulation of which leads to the onset of mitochondrial dysfunction and senescence in the progression of articular cartilage loss.