The CH25H–CYP7B1–RORα axis of cholesterol metabolism regulates osteoarthritis

Wan-Su Choi, Gyuseok Lee, Won-Hyun Song, Jeong-Tae Koh, Jiye Yang, Ji-Sun Kwak, Hyo-Eun Kim, Seul Ki Kim, Young-Ok Son, Hojung Nam, Iljung Jin, Zee-Yong Park, Jiyeon Kim, In Young Park, Jeong-Im Hong, Hyun Ah Kim, Churl-Hong Chun, Je-Hwang Ryu () and Jang-Soo Chun ()
Additional contact information
Wan-Su Choi: Gwangju Institute of Science and Technology
Gyuseok Lee: Gwangju Institute of Science and Technology
Won-Hyun Song: School of Dentistry, Chonnam National University
Jeong-Tae Koh: School of Dentistry, Chonnam National University
Jiye Yang: Gwangju Institute of Science and Technology
Ji-Sun Kwak: Gwangju Institute of Science and Technology
Hyo-Eun Kim: Gwangju Institute of Science and Technology
Seul Ki Kim: Gwangju Institute of Science and Technology
Young-Ok Son: Gwangju Institute of Science and Technology
Hojung Nam: Gwangju Institute of Science and Technology
Iljung Jin: Gwangju Institute of Science and Technology
Zee-Yong Park: Gwangju Institute of Science and Technology
Jiyeon Kim: Gwangju Institute of Science and Technology
In Young Park: Hallym University Sacred Heart Hospital
Jeong-Im Hong: Hallym University Sacred Heart Hospital
Hyun Ah Kim: Hallym University Sacred Heart Hospital
Churl-Hong Chun: Wonkwang University School of Medicine
Je-Hwang Ryu: School of Dentistry, Chonnam National University
Jang-Soo Chun: Gwangju Institute of Science and Technology

Nature, 2019, vol. 566, issue 7743, 254-258

Abstract: Abstract 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 investigated4–6. 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.

Date: 2019
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DOI: 10.1038/s41586-019-0920-1

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