Article

Calcified Tissue International

, Volume 82, Issue 6, pp 445-453

The Binding Between Sclerostin and LRP5 is Altered by DKK1 and by High-Bone Mass LRP5 Mutations

  • Wendy BalemansAffiliated withDepartment of Medical Genetics, University and University Hospital of Antwerp Email author 
  • , Elke PitersAffiliated withDepartment of Medical Genetics, University and University Hospital of Antwerp
  • , Erna CleirenAffiliated withDepartment of Medical Genetics, University and University Hospital of AntwerpDiscovery Lab Operations, Tibotec
  • , Minrong AiAffiliated withDepartment of Genetics, Case Western Reserve University
  • , Liesbeth Van WesenbeeckAffiliated withDepartment of Medical Genetics, University and University Hospital of Antwerp
  • , Matthew L. WarmanAffiliated withDepartment of Genetics, Case Western Reserve UniversityHoward Hughes Medical Institute, Orthopaedic Research Laboratories
  • , Wim Van HulAffiliated withDepartment of Medical Genetics, University and University Hospital of Antwerp

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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.

Keywords

LRP5 High bone mass Sclerostin DKK1