The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations.
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.
Department of Medical Genetics, University and University Hospital of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. wendy.balemans@ua.ac.be
Wendy
W
Balemans
Elke
E
Piters
Erna
E
Cleiren
Minrong
M
Ai
Liesbeth
L
Van Wesenbeeck
Matthew L
ML
Warman
Wim
W
Van Hul
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000737:chemistry; D005819:Genetic Markers; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D011485:Protein Binding; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; C422903:SOST protein, human