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<p>Osteoarthritis (OA) is the most common joint disease characterized by joint inflammation and cartilage deterioration. Though disrupted cholesterol metabolism has been implicated in the pathogenesis of OA, the underlying mechanisms remains unclear. Here we demonstrate that increased cholesterol in joint is a crucial activator of the cGAS-STING pathway in cartilage during OA. Subchondral osteocytes, which contact with blood vessel and cartilage, increase their uptake of cholesterol and transfer mitochondria to cartilage to trigger its inflammatory pathway. This process is mediated by increased cytosolic mitochondrial DNA (mtDNA) in chondrocytes, and is further amplified through enhanced mitochondrial transfer between chondrocytes. Mechanistically, we identify a mitochondrial subpopulation in osteocytes that enriched in Nudt8, which act as a key regulator of metabolic-inflammatory crosstalk. Nudt8 alters cholesterol metabolism by degrading coenzyme A, leading to an accumulation of cytosolic mtDNA and subsequent activation of the cGAS-STING pathway in chondrocytes. Pharmacological targeting osteocyte mitochondrial Nudt8 by supplementing pantethine ameliorate inflammation in cartilage and joint pain in OA mice, offering a potential therapeutic strategy for OA.</p>

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Mitochondria relay cholesterol signal exacerbates osteoarthritis in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • Yiyang Ma,
  • Yidan Pang,
  • Chenglong Liu,
  • Yuchen Tian,
  • Kaiwen Zheng,
  • Meng Yao,
  • Xiaofeng Liu,
  • Ruomu Cao,
  • Yiwei Zhao,
  • Zhikai Zheng,
  • Weitao Jia,
  • Daoyu Zhu,
  • Hao Peng,
  • Dajiang Du,
  • Xinhua Qu,
  • Chuan-ju Liu,
  • Pei Yang,
  • Yigang Huang,
  • Changqing Zhang,
  • Junjie Gao

摘要

Osteoarthritis (OA) is the most common joint disease characterized by joint inflammation and cartilage deterioration. Though disrupted cholesterol metabolism has been implicated in the pathogenesis of OA, the underlying mechanisms remains unclear. Here we demonstrate that increased cholesterol in joint is a crucial activator of the cGAS-STING pathway in cartilage during OA. Subchondral osteocytes, which contact with blood vessel and cartilage, increase their uptake of cholesterol and transfer mitochondria to cartilage to trigger its inflammatory pathway. This process is mediated by increased cytosolic mitochondrial DNA (mtDNA) in chondrocytes, and is further amplified through enhanced mitochondrial transfer between chondrocytes. Mechanistically, we identify a mitochondrial subpopulation in osteocytes that enriched in Nudt8, which act as a key regulator of metabolic-inflammatory crosstalk. Nudt8 alters cholesterol metabolism by degrading coenzyme A, leading to an accumulation of cytosolic mtDNA and subsequent activation of the cGAS-STING pathway in chondrocytes. Pharmacological targeting osteocyte mitochondrial Nudt8 by supplementing pantethine ameliorate inflammation in cartilage and joint pain in OA mice, offering a potential therapeutic strategy for OA.