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SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor.

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.

Pubmed ID: 15908424


  • Sem├źnov M
  • Tamai K
  • He X


The Journal of biological chemistry

Publication Data

July 22, 2005

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM057603

Mesh Terms

  • Animals
  • Body Patterning
  • Bone Diseases, Developmental
  • Bone Morphogenetic Proteins
  • Cell Line
  • Embryo, Mammalian
  • Embryo, Nonmammalian
  • Frizzled Receptors
  • Genetic Markers
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • LDL-Receptor Related Proteins
  • Ligands
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Protein Binding
  • Proteins
  • Receptors, LDL
  • Signal Transduction
  • Transfection
  • Wnt Proteins
  • Xenopus