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- Title
The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations.
- Authors
Balemans, Wendy; Piters, Elke; Cleiren, Erna; Ai, Minrong; Van Wesenbeeck, Liesbeth; Warman, Matthew L; Van Hul, Wim
- 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.
- Publication
Calcified tissue international, 2008, Vol 82, Issue 6, p445
- ISSN
0171-967X
- Publication type
Journal Article
- DOI
10.1007/s00223-008-9130-9