HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 50, 38276-38284, December 15, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/50/38276    most recent M609509200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Semenov, M. V. Articles by He, X. Search for Related Content PubMed PubMed Citation Articles by Semenov, M. V. Articles by He, X. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J.-M. Kaufman, A. Ostertag, A. Saint-Pierre, M. Cohen-Solal, A. Boland, I. Van Pottelbergh, K. Toye, M.-C. de Vernejoul, and M. Martinez Genome-Wide Linkage Screen of Bone Mineral Density (BMD) in European Pedigrees Ascertained through a Male Relative with Low BMD Values: Evidence for Quantitative Trait Loci on 17q21-23, 11q12-13, 13q12-14, and 22q11 J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3755 - 3762. [Abstract] [Full Text] [PDF]

				M. V. Semenov, X. Zhang, and X. He DKK1 Antagonizes Wnt Signaling without Promotion of LRP6 Internalization and Degradation J. Biol. Chem., August 1, 2008; 283(31): 21427 - 21432. [Abstract] [Full Text] [PDF]

				H K Datta, W F Ng, J A Walker, S P Tuck, and S S Varanasi The cell biology of bone metabolism J. Clin. Pathol., May 1, 2008; 61(5): 577 - 587. [Abstract] [Full Text] [PDF]

				A. G. Robling, P. J. Niziolek, L. A. Baldridge, K. W. Condon, M. R. Allen, I. Alam, S. M. Mantila, J. Gluhak-Heinrich, T. M. Bellido, S. E. Harris, et al. Mechanical Stimulation of Bone in Vivo Reduces Osteocyte Expression of Sost/Sclerostin J. Biol. Chem., February 29, 2008; 283(9): 5866 - 5875. [Abstract] [Full Text] [PDF]

				P. Leucht, J.-B. Kim, and J. A. Helms Beta-Catenin-Dependent Wnt Signaling in Mandibular Bone Regeneration J. Bone Joint Surg. Am., February 1, 2008; 90(Supplement_1): 3 - 8. [Abstract] [Full Text] [PDF]

				P. t. Dijke, C. Krause, D. J. J. de Gorter, C. W.G.M. Lowik, and R. L. van Bezooijen Osteocyte-Derived Sclerostin Inhibits Bone Formation: Its Role in Bone Morphogenetic Protein and Wnt Signaling J. Bone Joint Surg. Am., February 1, 2008; 90(Supplement_1): 31 - 35. [Abstract] [Full Text] [PDF]

				S. L. Dallas and L. F. Bonewald Osteocytes Emerging From Obscurity. Meeting Report from the 29th Annual Meeting of the American Society for Bone and Mineral Research: September 16-19, 2007 in Honolulu, Hawaii, USA IBMS BoneKEy, December 1, 2007; 4(12): 337 - 341. [Full Text] [PDF]

				R. Baron and G. Rawadi Targeting the Wnt/{beta}-Catenin Pathway to Regulate Bone Formation in the Adult Skeleton Endocrinology, June 1, 2007; 148(6): 2635 - 2643. [Abstract] [Full Text] [PDF]

				P. V. Bodine Wnt Signaling in Bone IBMS BoneKEy, March 1, 2007; 4(3): 108 - 123. [Abstract] [Full Text] [PDF]

				S. Ferrari Single Gene Mutations and Variations Affecting Bone Turnover and Strength: a Selective 2006 Update IBMS BoneKEy, December 1, 2006; 3(12): 11 - 29. [Abstract] [Full Text] [PDF]