Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4

Chenxi Cao, Yuanyuan Shi, Xin Zhang, Qi Li, Jiahao Zhang, Fengyuan Zhao, Qingyang Meng, Wenli Dai, Zhenlong Liu, Wenqiang Yan, Xiaoning Duan, Jiying Zhang, Xin Fu, Jin Cheng (), Xiaoqing Hu () and Yingfang Ao ()
Additional contact information
Chenxi Cao: Peking University Third Hospital
Yuanyuan Shi: Peking University Third Hospital
Xin Zhang: Peking University Third Hospital
Qi Li: Peking University Third Hospital
Jiahao Zhang: Peking University Third Hospital
Fengyuan Zhao: Peking University Third Hospital
Qingyang Meng: Peking University Third Hospital
Wenli Dai: Peking University Third Hospital
Zhenlong Liu: Peking University Third Hospital
Wenqiang Yan: Peking University Third Hospital
Xiaoning Duan: Peking University Third Hospital
Jiying Zhang: Peking University Third Hospital
Xin Fu: Peking University Third Hospital
Jin Cheng: Peking University Third Hospital
Xiaoqing Hu: Peking University Third Hospital
Yingfang Ao: Peking University Third Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Emerging evidence suggests that osteoarthritis is associated with high cholesterol levels in some osteoarthritis patients. However, the specific mechanism under this metabolic osteoarthritis phenotype remains unclear. We find that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse’s cartilage. By using Lrp3−/− mice in vivo and LRP3 lentiviral-transduced chondrocytes in vitro, we identify that LRP3 positively regulate chondrocyte extracellular matrix metabolism, and its deficiency aggravate the degeneration of cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuate anterior cruciate ligament transection induced osteoarthritis progression in rats and Lrp3 knockout-induced osteoarthritis progression in mice. LRP3 knockdown upregulate syndecan-4 by activating the Ras signaling pathway. We identify syndecan-4 as a downstream molecular target of LRP3 in osteoarthritis pathogenesis. These findings suggest that cholesterol-LRP3- syndecan-4 axis plays critical roles in osteoarthritis development, and LRP3 gene therapy may provide a therapeutic regimen for osteoarthritis treatment.

Date: 2022
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DOI: 10.1038/s41467-022-34830-4

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