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Calcif Tissue Int. 2008 Jun;82(6):445-53. doi: 10.1007/s00223-008-9130-9.

The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations.

Author information

  • 1Department of Medical Genetics, University and University Hospital of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. wendy.balemans@ua.ac.be

Abstract

Low-density lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor, plays an important role in bone metabolism as loss-of-function and gain-of-function mutations in LRP5 result in the autosomal recessive osteoporosis-pseudoglioma syndrome and autosomal dominant high-bone mass (HBM) phenotypes, respectively. Prior studies suggested that the presence of HBM-associated LRP5 mutations results in decreased antagonism of LRP5-mediated Wnt signaling. In the present study, we investigated six different HBM-LRP5 mutations and confirm that neither Dickkopf1 (DKK1) nor sclerostin efficiently inhibits HBM-LRP5 signaling. In addition, when coexpressed, DKK1 and sclerostin do not inhibit HBM-LRP5 mutants better than either inhibitor by itself. Also, DKK1 and sclerostin do not simultaneously bind to wild-type LRP5, and DKK1 is able to displace sclerostin from previously formed sclerostin-LRP5 complexes. In conclusion, our results indicate that DKK1 and sclerostin are independent, and not synergistic, regulators of LRP5 signaling and that the function of each is impaired by HBM-LRP5 mutations.

PMID:
18521528
[PubMed - indexed for MEDLINE]
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