Title
The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass **LRP5** mutations
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
New York ,
Subject
Human medicine
Source (journal)
Calcified tissue international. - New York
Volume/pages
82(2008) :6 , p. 445-453
ISSN
0171-967X
ISI
000257869700005
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Low-density lipoprotein receptorrelated 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 highbone 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 sclerostinLRP5 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.
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