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

被引：294

作者：

Choi, Wan-Su ^{[1
,2
]}

Lee, Gyuseok ^{[1
,2
,3
]}

Song, Won-Hyun ^{[3
]}

Koh, Jeong-Tae ^{[3
]}

Yang, Jiye ^{[1
,2
]}

Kwak, Ji-Sun ^{[1
,2
]}

Kim, Hyo-Eun ^{[1
,2
]}

Kim, Seul Ki ^{[1
,2
]}

Son, Young-Ok ^{[1
,2
]}

Nam, Hojung ^{[4
]}

Jin, Iljung ^{[4
]}

Park, Zee-Yong ^{[5
]}

Kim, Jiyeon ^{[5
]}

Park, In Young ^{[6
]}

Hong, Jeong-Im ^{[6
]}

Kim, Hyun Ah ^{[6
]}

Chun, Churl-Hong ^{[7
]}

Ryu, Je-Hwang ^{[3
]}

Chun, Jang-Soo ^{[1
,2
]}

机构：

[1] Gwangju Inst Sci & Technol, Natl Creat Res Initiat Ctr Osteoarthritis Pathoge, Gwangju, South Korea

[2] Gwangju Inst Sci & Technol, Sch Life Sci, Gwangju, South Korea

[3] Chonnam Natl Univ, Sch Dent, Dept Pharmacol & Dent Therapeut, Gwangju, South Korea

[4] Gwangju Inst Sci & Technol, Sch Elect Engn & Comp Sci, Gwangju, South Korea

[5] Gwangju Inst Sci & Technol, Sch Life Sci, Gwangju, South Korea

[6] Hallym Univ, Div Rheumatol, Sacred Heart Hosp, Kyunggido, South Korea

[7] Wonkwang Univ, Dept Orthoped Surg, Sch Med, Iksan, South Korea

来源：

NATURE | 2019年 / 566卷 / 7743期

基金：

新加坡国家研究基金会;

关键词：

RECEPTOR ROR-ALPHA; CARTILAGE; PATHOGENESIS; DEGRADATION; OXYSTEROLS; MODEL; MICE;

D O I：

10.1038/s41586-019-0920-1

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Osteoarthritis-the most common form of age-related degenerative whole-joint disease(1)-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(4-6). 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-ROR alpha 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 (ROR alpha) 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-ROR alpha axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.

引用

页码：254 / +

页数：20

共 38 条

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