Parathyroid hormone signaling through low-density lipoprotein-related protein 6.
Intermittent administration of PTH stimulates bone formation, but the precise mechanisms responsible for PTH responses in osteoblasts are only incompletely understood. Here we show that binding of PTH to its receptor PTH1R induced association of LRP6, a coreceptor of Wnt, with PTH1R. The formation of the ternary complex containing PTH, PTH1R, and LRP6 promoted rapid phosphorylation of LRP6, which resulted in the recruitment of axin to LRP6, and stabilization of beta-catenin. Activation of PKA is essential for PTH-induced beta-catenin stabilization, but not for Wnt signaling. In vivo studies confirmed that PTH treatment led to phosphorylation of LRP6 and an increase in amount of beta-catenin in osteoblasts with a concurrent increase in bone formation in rat. Thus, LRP6 coreceptor is a key element of the PTH signaling that regulates osteoblast activity.
Wan
Mei
M
Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. mwan@uab.edu
Yang
Chaozhe
C
Li
Jun
J
Wu
Xiangwei
X
Yuan
Hongling
H
Ma
Hairong
H
He
Xi
X
Nie
Shuyi
S
Chang
Chenbei
C
Cao
Xu
X
D000818:Animals; D060466:Axin Protein; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D010281:Parathyroid Hormone / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin / Q000378:metabolism
D060466:Axin Protein; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; C555477:Lrp6 protein, rat; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D011973:Receptors, LDL; D012097:Repressor Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D017868:Cyclic AMP-Dependent Protein Kinases