The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis
The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis
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DOI：
10.1038/s41586-019-0920-1
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发表时间：
2019-02-14
期刊：
影响因子：
64.8
通讯作者：
Chun, Jang-Soo
中科院分区：
文献类型：
--
作者：
Choi, Wan-Su;Lee, Gyuseok;Chun, Jang-Soo
骨关节炎-最常见的年龄相关性退行性全关节疾病（1）-主要特征为软骨破坏，以及滑膜炎症，骨赘形成和软骨下骨重塑（2，3）。然而，骨关节炎发病机制的分子机制在很大程度上是未知的。虽然骨关节炎目前被认为与代谢紊乱有关，但缺乏直接证据，胆固醇代谢在骨关节炎发病机制中的作用尚未得到充分研究（4-6）。各种类型的胆固醇羟化酶通过将细胞胆固醇转化为循环氧化固醇，从而调节各种生物过程，从而促进肝外组织中的胆固醇代谢（7，8）。在这里，我们表明，在软骨细胞中的胆固醇代谢的CH 25 H-CYP 7 B1-ROR α轴是骨关节炎的发病机制的一个重要的分解代谢调节剂。骨关节炎软骨细胞的胆固醇水平增加，因为增强的摄取，上调胆固醇羟化酶（CH 25 H和CYP 7 B1）和氧化固醇代谢产物的产生增加。在小鼠关节组织中CH 25 H或CYP 7 B1的腺病毒过表达引起实验性骨关节炎，而敲除或敲低这些羟化酶消除了骨关节炎的发病机制。此外，发现视黄酸相关孤儿受体α（ROR α）通过胆固醇代谢的改变介导骨关节炎的诱导。这些结果表明，骨关节炎是一种与代谢紊乱相关的疾病，并表明靶向胆固醇代谢的CH 25 H-CYP 7 B1-ROR α轴可能为治疗骨关节炎提供治疗途径。
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.