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J. Biol. Chem., Vol. 281, Issue 50, 38276-38284, December 15, 2006
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LRP5 Mutations Linked to High Bone Mass Diseases Cause Reduced LRP5 Binding and Inhibition by SOST*
From the Neurobiology Program, Children's Hospital Boston and Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115
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.
Received for publication, May 1, 2006 , and in revised form, October 10, 2006.
* This work was supported in part by Grant RO1GM57603 from the National Institutes of Health (to X. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence may be addressed: Division of Neuroscience, Enders 470, Children's Hospital, 61 Binney St., Boston, MA 02115. Tel.: 617-919-2260 (2257); Fax: 617-730-1953; E-mail: mikhail.semenov{at}childrens.harvard.edu. 2 W. M. Keck Foundation Distinguished Young Scholar and a Leukemia and Lymphoma Society Scholar. To whom correspondence may be addressed: Division of Neuroscience, Children's Hospital, 61 Binney St., Boston, MA 02115. Tel.: 617-919-2260 (2257); Fax: 617-730-1953; E-mail: xi.he{at}childrens.harvard.edu.
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