title: Antagonists of LRP6 regulate PTH-induced cAMP generation.
abstract: 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.
authors.affiliation: Shihezi Medical College, Shihezi University, Xinjiang, China.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Shi
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Weishan
authors.initials: W
authors.lastname: Wang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Cao
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis*; D005269:Femur / Q000187:drug effects / Q000502:physiology; D006023:Glycoproteins / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000494:pharmacology / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501127:Dkk1 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D010281:Parathyroid Hormone; C486030:Sost protein, mouse; D000242:Cyclic AMP