LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST

被引:171
|
作者
Semenov, Mikhail V.
He, Xi
机构
[1] Childrens Hosp, Div Neurosci, Neurobiol Program, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA
关键词
D O I
10.1074/jbc.M609509200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The low density lipoprotein (LDL) receptor-related protein 5 (LRP5) is a co-receptor for Wnt proteins and a major regulator in bone homeostasis. Human genetic studies have shown that recessive loss-of-function mutations in LRP5 are linked to osteoporosis, while on the contrary, dominant missense LRP5 mutations are associated with high bone mass (HBM) diseases. All LRP5 HBM mutations are clustered in a single region in the LRP5 extracellular domain and presumably result in elevated Wnt signaling in bone forming cells. Here we show that LRP5 HBM mutant proteins exhibit reduced binding to a secreted bone-specific LRP5 antagonist, SOST, and consequently are more refractory to inhibition by SOST. As loss-of-function mutations in the SOST gene are associated with Sclerosteosis, another disorder of excessive bone growth, our study suggests that the SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases.
引用
收藏
页码:38276 / 38284
页数:9
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