한빛사 논문
Wan-Su Choi1,7, Gyuseok Lee1,2,7, Won-Hyun Song2, Jeong-Tae Koh2, Jiye Yang1, Ji-Sun Kwak1, Hyo-Eun Kim1, Seul Ki Kim1, Young-Ok Son1, Hojung Nam3, Iljung Jin3, Zee-Yong Park4, Jiyeon Kim4, In Young Park5, Jeong-Im Hong5, Hyun Ah Kim5, Churl-Hong Chun6, Je-Hwang Ryu2,* & Jang-Soo Chun1,*
1 National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea. 2 Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, South Korea. 3 School of Electrical Engineering and Computer Science, Gwangju Institute of Science and Technology, Gwangju, South Korea. 4 School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea. 5 Division of Rheumatology, Hallym University Sacred Heart Hospital, Kyunggido, South Korea. 6 Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, South Korea. 7 These authors contributed equally: Wan-Su Choi, Gyuseok Lee.
*Correspondence to Je-Hwang Ryu or Jang-Soo Chun
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 remodelling 2,3. 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 investigated 4,5,6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes 7,8. 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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