Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4.
Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4.
复制标题
胆固醇诱导的LRP 3下调通过靶向Syndecan-4促进骨关节炎中的软骨退变
DOI：
10.1038/s41467-022-34830-4
复制
发表时间：
2022-11-21
影响因子：
16.6
通讯作者：
Ao, Yingfang
中科院分区：
文献类型：
--
作者：
Cao, Chenxi;Shi, Yuanyuan;Zhang, Xin;Li, Qi;Zhang, Jiahao;Zhao, Fengyuan;Meng, Qingyang;Dai, Wenli;Liu, Zhenlong;Yan, Wenqiang;Duan, Xiaoning;Zhang, Jiying;Fu, Xin;Cheng, Jin;Hu, Xiaoqing;Ao, Yingfang
新出现的证据表明，在一些骨关节炎患者中，骨关节炎与高胆固醇水平有关。然而，这种代谢性骨关节炎表型的具体机制仍不清楚。我们发现，在高胆固醇饮食的小鼠软骨中，胆固醇代谢相关基因LRP3(低密度脂蛋白受体相关蛋白3)显著减少。通过体内LRP3−/−小鼠和LRP3慢病毒转导软骨细胞的体外实验，我们发现LRP3对软骨细胞的细胞外基质代谢有正向调节作用，LRP3的缺失加剧了软骨的退变。无论饮食如何，在软骨中过表达LRP3可以延缓前交叉韧带切断导致的大鼠骨关节炎进展和LRP3基因敲除导致的小鼠骨关节炎进展。LRP3基因敲除通过激活RAS信号通路上调syndecan-4的表达。我们发现Syndecan-4是LRP3在骨关节炎发病机制中的下游分子靶点。这些发现提示胆固醇-LRP3-Syndecan-4轴在骨关节炎的发生发展中起关键作用，LRP3基因治疗可能为骨关节炎的治疗提供一种治疗方案。本研究证实了胆固醇代谢相关基因Lrp3在软骨退变和骨性关节炎发病机制中的作用。LRP3通过RAS信号转导靶向Syndecan-4，正向调节软骨细胞外基质代谢，提示胆固醇-LRP3-SDC4轴参与了骨关节炎软骨退变。
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. This study demonstrates a role of cholesterol metabolism-related gene, Lrp3, in cartilage degeneration and osteoarthritis pathogenesis. LRP3 positively regulates cartilage extracellular matrix metabolism by targeting syndecan-4 via Ras signalling, implicating the cholesterol-LRP3-SDC4 axis in osteoarthritic cartilage degeneration.
登录
查看更多内容
影响因子：
7
作者：
Barre, PE;Redini, F;Pujol, JP
通讯作者：
Pujol, JP
影响因子：
7
作者：
Brunner, A. M.;Henn, C. M.;Ehrlich, M. G.
通讯作者：
Ehrlich, M. G.
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
影响因子：
3.9
作者：
Cho BW;Kim DS;Kwon HM;Yang IH;Lee WS;Park KK
通讯作者：
Park KK
影响因子：
4.4
作者：
Ishii, H;Kim, DH;Yamamoto, TT
通讯作者：
Yamamoto, TT