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N-cadherin Restrains PTH Activation of Lrp6/β-catenin Signaling and Osteoanabolic Action
- Source :
- Journal of Bone and Mineral Research. 30:274-285
- Publication Year :
- 2015
- Publisher :
- Wiley, 2015.
-
Abstract
- Interaction between parathyroid hormone/parathyroid hormone-related peptide receptor 1 (PTHR1) and low-density lipoprotein receptor-related protein 6 (Lrp6) is important for parathyroid hormone (PTH) signaling and anabolic action. Because N-cadherin has been shown to negatively regulate canonical Wnt/β-catenin signaling, we asked whether N-cadherin alters PTH signaling and stimulation of bone formation. Ablation of the N-cadherin gene (Cdh2) in primary osteogenic lineage cells resulted in increased Lrp6/PTHR1 interaction in response to PTH1-34 , associated with enhanced PTH-induced PKA signaling and PKA-dependent β-catenin C-terminus phosphorylation, which promotes β-catenin transcriptional activity. β-catenin C-terminus phosphorylation was abolished by Lrp6 knockdown. Accordingly, PTH1-34 stimulation of Tcf/Lef target genes, Lef1 and Axin2, was also significantly enhanced in Cdh2-deficient cells. This enhanced responsiveness to PTH extends to the osteo-anabolic effect of PTH, as mice with a conditional Cdh2 deletion in Osx+ cells treated with intermittent doses of PTH1-34 exhibited significantly larger gains in trabecular bone mass relative to control mice, the result of accentuated osteoblast activity. Therefore, N-cadherin modulates Lrp6/PTHR1 interaction, restraining the intensity of PTH-induced β-catenin signaling, and ultimately influencing bone formation in response to intermittent PTH administration.
- Subjects :
- medicine.medical_specialty
Beta-catenin
Endocrinology, Diabetes and Metabolism
Wnt signaling pathway
Parathyroid hormone
LRP6
Osteoblast
Biology
TCF/LEF family
Endocrinology
medicine.anatomical_structure
Internal medicine
biology.protein
medicine
Phosphorylation
Orthopedics and Sports Medicine
Signal transduction
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 08840431
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Journal of Bone and Mineral Research
- Accession number :
- edsair.doi...........2b5201d4560a7822dfc0640d5405fd97