Mitochondria relay cholesterol signal exacerbates osteoarthritis in mice

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 () and Junjie Gao ()
Additional contact information
Yiyang Ma: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Yidan Pang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Chenglong Liu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Yuchen Tian: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Kaiwen Zheng: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Meng Yao: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Xiaofeng Liu: Shanghai Sixth People’s Hospital Fujian, Quanzhou, Department of Orthopaedic Surgery
Ruomu Cao: the Second Affiliated Hospital of Xi’an Jiaotong University, Department of Bone and Joint Surgery
Yiwei Zhao: the Second Affiliated Hospital of Xi’an Jiaotong University, Department of Bone and Joint Surgery
Zhikai Zheng: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Weitao Jia: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Daoyu Zhu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Hao Peng: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Dajiang Du: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Xinhua Qu: Shanghai Jiaotong University School of Medicine, Department of Bone and Joint Surgery, Renji Hospital
Chuan-ju Liu: Yale University School of Medicine, Department of Orthopaedics and Rehabilitation
Pei Yang: the Second Affiliated Hospital of Xi’an Jiaotong University, Department of Bone and Joint Surgery
Yigang Huang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Changqing Zhang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery
Junjie Gao: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopaedic Surgery

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65689-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65689-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65689-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().