Mitochondria relay cholesterol signal exacerbates osteoarthritis in mice
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.
Authors
- Dajiang Du (ORCID: https://orcid.org/0000-0002-4204-9721)
- Kaiwen Zheng (ORCID: https://orcid.org/0000-0003-3184-5375)
- Junjie Gao (ORCID: https://orcid.org/0000-0003-4820-8524)
- Hao Peng (ORCID: https://orcid.org/0000-0003-1915-6104)
- Weitao Jia (ORCID: https://orcid.org/0000-0001-9363-5598)
- Ruomu Cao
- Yiwei Zhao
- C.-J. Liu (ORCID: https://orcid.org/0000-0002-7181-8032)
- Yidan Pang (ORCID: https://orcid.org/0000-0002-2286-1069)
- Yiyang Ma (ORCID: https://orcid.org/0000-0002-6218-8593)
- Yuchen Tian (ORCID: https://orcid.org/0000-0002-5632-9118)
- Xinhua Qu (ORCID: https://orcid.org/0000-0002-8889-0890)
- Chenglong Liu (ORCID: https://orcid.org/0000-0002-3064-2595)
- Yigang Huang
- Daoyu Zhu (ORCID: https://orcid.org/0000-0001-6276-1233)
- Pei Yang (ORCID: https://orcid.org/0000-0002-0466-2875)
- Meng Yao (ORCID: https://orcid.org/0000-0001-7645-0196)
- Xiaofeng Liu (ORCID: https://orcid.org/0000-0002-4514-2016)
- Changqing Zhang (ORCID: https://orcid.org/0000-0002-7408-4126)
- Zhikai Zheng
Institutions
- Shanghai Jiao Tong University (CN)
- Renji Hospital (CN)
- Yale University (US)
- The 180th Hospital of PLA (CN)
- Second Affiliated Hospital of Xi'an Jiaotong University (CN)
- Shanghai Sixth People's Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-19
- DOI
- https://doi.org/10.1038/s41467-025-65689-w
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Shanghai Rising-Star Program
- National Key Research and Development Program of China