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

Abstract

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.

• Authors: Mikhail V Semenov, Xi He
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 50 Pg. 38276-84 (Dec 15 2006) ISSN: 0021-9258 [Print] United States
• PMID: 17052975 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Bone Morphogenetic Proteins
• DNA, Complementary
• Genetic Markers
• LDL-Receptor Related Proteins
• LRP5 protein, human
• Low Density Lipoprotein Receptor-Related Protein-5
• SOST protein, human

Topics

• Adaptor Proteins, Signal Transducing
• Bone Diseases (genetics, metabolism)
• Bone Morphogenetic Proteins (genetics, metabolism)
• Cell Line
• DNA, Complementary
• Genetic Markers (genetics)
• Humans
• LDL-Receptor Related Proteins (genetics, metabolism)
• Low Density Lipoprotein Receptor-Related Protein-5
• Mutation
• Protein Binding