Osteoarthritis—the most common form of age-related degenerative whole-joint disease1—is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated4,5,6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes7,8. Here we show that the CH25H–CYP7B1–RORα axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (RORα) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H–CYP7B1–RORα axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.
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Microarray data have been deposited in the Gene Expression Omnibus under accession codes GSE104793 (for IL-1β), GSE104794 (for HIF-2α), and GSE104795 (for ZIP8). Source Data for the Figures and Extended Data Figures are provided in the online version of the paper. Uncropped images of western blots and gels are available in the Supplementary Information.
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This work was supported by grants from the National Research Foundation of Korea (2016R1A3B1906090 and 2016R1A5A1007318 to J.-S.C., 2012R1A5A2A39671455 and 2018R1A2B2006033 to J.-H.R., and 2017R1A6A3A11034719 to W.-S.C.), the Korea Healthcare Technology R&D project of the Korea Health Industry Development Institute (HI16C0287 to J-.S.C., J.-H.R. and H.A.K., and H114C3484 to J.-S.C. and J.-H.R.), and the GIST Research Institute (GRI) to J.-S.C.
Nature thanks Benjamin Alman and the other anonymous reviewer(s) for their contribution to the peer review of this work.