Cholesterol metabolism regulates cartilage metabolic-inflammatory crosstalk by triggering osteocyte mitochondria transfer as a therapeutic target for osteoarthritis

Osteoarthritis (OA) is considered as a metabolic related inflammatory disease in the joint affecting both cartilage and subchondral bone. Cholesterol metabolism has been implicated in the pathogenesis of OA, yet the underlying mechanism still remains elusive. Understanding the role of cholesterol metabolism in the joint inflammation will provide treatment alternatives of OA. Here, we found that the disordered cholesterol metabolism in joint do not directly target cartilage and synovium but target subchondral bone by transferring osteocyte mitochondria to amplify inflammatory phenotype in the cartilage. In detail, Nudt8 in osteocyte mitochondria serves as a metabolic-inflammatory switch point to alter cholesterol metabolism by degrading coenzyme A (CoA) and further increase the cytosolic mitochondrial DNA (mtDNA) stress to activate cGAS-STING pathway in chondrocytes, resulting in exacerbated inflammation and OA severity. Inhibiting the transfer of osteocyte mitochondria ameliorated joint inflammation and OA progression. Pharmacological targeting osteocyte mitochondria regulated cholesterol metabolism by supplementation of pantethine - an important precursor metabolite of CoA - ameliorated osteocyte mitochondria activated cGAS-STING pathway and OA phenotype in chondrocytes, and subsequent improved the joint damage and reduced painful behavior in OA mice. Targeting cholesterol-mitochondria regulated metabolic-inflammatory crosstalk represents a promising treatment strategy for OA.