Antagonists of LRP6 regulate PTH-induced cAMP generation

Chenhui Shi, Jun Li, Weishan Wang, Weiwei Cao, Xu Cao, Mei Wan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


LRP6 is a common coreceoptor for different G protein-coupled seven-transmembrane receptors in production of cAMP. Extracelluar proteins sclerostin and DKK1, initially identified as antagonists for Wnt signaling by binding to LRP6, are negative regulators for bone formation. Here, we show that both sclerostin and DKK1 inhibit PTH-stimulated cAMP production. In addition, PTH suppresses expression of sclerostin in osteocytes in mice. We also found that sclerostin and DKK1 binds to LRP6 as antagonists to increase the availability of LRP6 to facilitate PTH signaling in a positive-feedback fashion. These studies reveal a previously unrecognized function of sclerostin and DKK1, which provides an alternative explanation for the application of sclerostin and DKK1 neutralization on enhancing bone formation as a potential therapy for skeletal diseases.

Original languageEnglish (US)
Pages (from-to)39-46
Number of pages8
JournalAnnals of the New York Academy of Sciences
Issue number1
StatePublished - Nov 2011


  • CAMP production
  • DKK1
  • LRP6
  • PTH
  • Sclerostin

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • History and Philosophy of Science


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