Parathyroid Hormone Signaling Through Low-density Lipoprotein-related Protein 6

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2008 Nov 5

PMID 18981475

Citations 131

Authors

Mei Wan

Chaozhe Yang

Jun Li

Xiangwei Wu

Hongling Yuan

Hairong Ma

Xi He

Shuyi Nie

Chenbei Chang

Xu Cao

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Evaluation of Prenatal Transportation Stress on DNA Methylation (DNAm) and Gene Expression in the Hypothalamic-Pituitary-Adrenal (HPA) Axis Tissues of Mature Brahman Cows.

Earnhardt-San A, Baker E, Cilkiz K, Cardoso R, Ghaffari N, Long C Genes (Basel). 2025; 16(2).

PMID: 40004522 PMC: 11855312. DOI: 10.3390/genes16020191.

Signaling Pathways Driving MSC Osteogenesis: Mechanisms, Regulation, and Translational Applications.

Wang L, Ruan M, Bu Q, Zhao C Int J Mol Sci. 2025; 26(3).

PMID: 39941080 PMC: 11818554. DOI: 10.3390/ijms26031311.

Palm Tocotrienol Activates the Wnt3a/β-Catenin Signaling Pathway, Protecting MC3T3-E1 Osteoblasts from Cellular Damage Caused by Dexamethasone and Promoting Bone Formation.

Abdullah Sani N, Kamaruddin N, Soelaiman I, Pang K, Chin K, Ramli E Biomedicines. 2025; 13(1).

PMID: 39857826 PMC: 11762645. DOI: 10.3390/biomedicines13010243.

Differential bone and vessel type formation at superior and dura periosteum during cranial bone defect repair.

Zhai Y, Zhou Z, Xing X, Nuzzle M, Zhang X Bone Res. 2025; 13(1):8.

PMID: 39805832 PMC: 11729862. DOI: 10.1038/s41413-024-00379-9.

A Huluwa phosphorylation switch regulates embryonic axis induction.

Li Y, Yan Y, Gong B, Zheng Q, Zhou H, Sun J Nat Commun. 2024; 15(1):10028.

PMID: 39562571 PMC: 11576741. DOI: 10.1038/s41467-024-54450-4.

References

Li Y, Marzolo M, van Kerkhof P, Strous G, Bu G . The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. J Biol Chem. 2000; 275(22):17187-94. DOI: 10.1074/jbc.M000490200. View

Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J . Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005; 280(20):19883-7. DOI: 10.1074/jbc.M413274200. View

Pinson K, Brennan J, Monkley S, Avery B, Skarnes W . An LDL-receptor-related protein mediates Wnt signalling in mice. Nature. 2000; 407(6803):535-8. DOI: 10.1038/35035124. View

Mao J, Wang J, Liu B, Pan W, Farr 3rd G, Flynn C . Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell. 2001; 7(4):801-9. DOI: 10.1016/s1097-2765(01)00224-6. View

Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A . LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature. 2001; 411(6835):321-5. DOI: 10.1038/35077108. View

Bafico A, Liu G, Yaniv A, Gazit A, Aaronson S . Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol. 2001; 3(7):683-6. DOI: 10.1038/35083081. View

Semenov M, Tamai K, Brott B, Kuhl M, Sokol S, He X . Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol. 2001; 11(12):951-61. DOI: 10.1016/s0960-9822(01)00290-1. View

Huelsken J, Birchmeier W . New aspects of Wnt signaling pathways in higher vertebrates. Curr Opin Genet Dev. 2001; 11(5):547-53. DOI: 10.1016/s0959-437x(00)00231-8. View

Staal F, Clevers H . Tcf/Lef transcription factors during T-cell development: unique and overlapping functions. Hematol J. 2002; 1(1):3-6. DOI: 10.1038/sj.thj.6200001. View

10.

Moon R, Bowerman B, Boutros M, Perrimon N . The promise and perils of Wnt signaling through beta-catenin. Science. 2002; 296(5573):1644-6. DOI: 10.1126/science.1071549. View

11.

Pierce K, Premont R, Lefkowitz R . Seven-transmembrane receptors. Nat Rev Mol Cell Biol. 2002; 3(9):639-50. DOI: 10.1038/nrm908. View

12.

Qin L, Qiu P, Wang L, Li X, Swarthout J, Soteropoulos P . Gene expression profiles and transcription factors involved in parathyroid hormone signaling in osteoblasts revealed by microarray and bioinformatics. J Biol Chem. 2003; 278(22):19723-31. DOI: 10.1074/jbc.M212226200. View

13.

Winkler D, Sutherland M, Geoghegan J, Yu C, Hayes T, Skonier J . Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003; 22(23):6267-76. PMC: 291840. DOI: 10.1093/emboj/cdg599. View

14.

Tamai K, Zeng X, Liu C, Zhang X, Harada Y, Chang Z . A mechanism for Wnt coreceptor activation. Mol Cell. 2004; 13(1):149-56. DOI: 10.1016/s1097-2765(03)00484-2. View

15.

van Bezooijen R, Roelen B, Visser A, van der Wee-Pals L, de Wilt E, Karperien M . Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004; 199(6):805-14. PMC: 2212719. DOI: 10.1084/jem.20031454. View

16.

Qin L, Raggatt L, Partridge N . Parathyroid hormone: a double-edged sword for bone metabolism. Trends Endocrinol Metab. 2004; 15(2):60-5. DOI: 10.1016/j.tem.2004.01.006. View

17.

He X, Semenov M, Tamai K, Zeng X . LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development. 2004; 131(8):1663-77. DOI: 10.1242/dev.01117. View

18.

Logan C, Nusse R . The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004; 20:781-810. DOI: 10.1146/annurev.cellbio.20.010403.113126. View

19.

Potts Jr J, Murray T, Peacock M, Niall H, Tregear G, Keutmann H . Parathyroid hormone: sequence, synthesis, immunoassay studies. Am J Med. 1971; 50(5):639-49. DOI: 10.1016/0002-9343(71)90119-7. View

20.

Tregear G, Van Rietschoten J, Greene E, Keutmann H, Niall H, Reit B . Bovine parathyroid hormone: minimum chain length of synthetic peptide required for biological activity. Endocrinology. 1973; 93(6):1349-53. DOI: 10.1210/endo-93-6-1349. View