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J. Biol. Chem., Vol. 280, Issue 29, 26770-26775, July 22, 2005

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SOST Is a Ligand for LRP5/LRP6 and a Wnt Signaling Inhibitor^*

Mikhail Semënov, Keiko Tamai, and Xi He¶

From the Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Sclerosteosis is an autosomal recessive disease that is characterized by overgrowth of bone tissue and is linked to mutations in the gene encoding the secreted protein SOST. Sclerosteosis shares remarkable similarities with "high bone mass" diseases caused by "gain-of-function" mutations in the LRP5 gene, which encodes a coreceptor for Wnt signaling proteins. We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. Our findings suggest that SOST is an antagonist for Wnt signaling and that the loss of SOST function likely leads to the hyperactivation of Wnt signaling that underlies bone overgrowth seen in sclerosteosis patients.

Received for publication, April 20, 2005 , and in revised form, May 16, 2005.

Addendum—While this manuscript was in preparation, Li et al. also reported that SOST can bind to LRP5/6 and function as a Wnt signaling antagonist (42).

^* This work was supported in part by National Institutes of Health Grant GM057603 (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.

Partially supported by research fellowship from the Uehara Memorial Foundation.

^¶ W. M. Keck Foundation Distinguished Young Scholar in Medical Research.

To whom correspondence may be addressed: Division of Neuroscience, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-919-2260 or 617-355-6885; Fax: 617-730-0243; E-mail: mikhail.semenov{at}childrens.harvard.edu or xi.he{at}childrens.harvard.edu.

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