骨关节炎
软骨
下调和上调
基因敲除
软骨细胞
医学
胆固醇
内分泌学
基因剔除小鼠
内科学
癌症研究
细胞生物学
生物
受体
病理
解剖
生物化学
基因
替代医学
作者
Canhui Cao,Yuanyuan Shi,Xin Zhang,Qi Li,Jiahao Zhang,Fengyuan Zhao,Qiong Meng,Weihui Dai,Zhenlong Liu,Wenqiang Yan,Xin Duan,Jiying Zhang,Xin Fu,Jin Cheng,Xiaoqing Hu,Yingfang Ao
标识
DOI:10.1038/s41467-022-34830-4
摘要
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.
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