These authors contributed equally to this work.
Antagonists of LRP6 regulate PTH-induced cAMP generation
Article first published online: 14 NOV 2011
© 2011 New York Academy of Sciences.
Annals of the New York Academy of Sciences
Volume 1237, Skeletal Biology and Medicine I pages 39–46, November 2011
How to Cite
Shi, C., Li, J., Wang, W., Cao, W., Cao, X. and Wan, M. (2011), Antagonists of LRP6 regulate PTH-induced cAMP generation. Annals of the New York Academy of Sciences, 1237: 39–46. doi: 10.1111/j.1749-6632.2011.06226.x
- Issue published online: 14 NOV 2011
- Article first published online: 14 NOV 2011
- cAMP production
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.