2. Academic Validation
  3. Mitochondria relay cholesterol signal exacerbates osteoarthritis in mice

Mitochondria relay cholesterol signal exacerbates osteoarthritis in mice

  • Nat Commun. 2025 Nov 19;16(1):10123. doi: 10.1038/s41467-025-65689-w.
Yiyang Ma # 1 2,  Yidan Pang # 1 2,  Chenglong Liu # 1 2,  Yuchen Tian # 1 2,  Kaiwen Zheng 1 2,  Meng Yao 1 2,  Xiaofeng Liu 3,  Ruomu Cao 4,  Yiwei Zhao 4,  Zhikai Zheng 1 2,  Weitao Jia 1 2,  Daoyu Zhu 1,  Hao Peng 1,  Dajiang Du 1,  Xinhua Qu 5,  Chuan-Ju Liu 6,  Pei Yang 7,  Yigang Huang 8 9,  Changqing Zhang 10 11,  Junjie Gao 12 13
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Fujian, Quanzhou, Fujian, China.
  • 4 Department of Bone and Joint Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China.
  • 5 Department of Bone and Joint Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 6 Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.
  • 7 Department of Bone and Joint Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China. [email protected].
  • 8 Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 9 Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 10 Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 11 Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 12 Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 13 Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41257852 DOI: 10.1038/s41467-025-65689-w
Abstract

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.

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