| First Author | Revollo L | Year | 2015 |
| Journal | J Bone Miner Res | Volume | 30 |
| Issue | 2 | Pages | 274-85 |
| PubMed ID | 25088803 | Mgi Jnum | J:302800 |
| Mgi Id | MGI:6510081 | Doi | 10.1002/jbmr.2323 |
| Citation | Revollo L, et al. (2015) N-cadherin restrains PTH activation of Lrp6/beta-catenin signaling and osteoanabolic action. J Bone Miner Res 30(2):274-85 |
| abstractText | 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/beta-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 beta-catenin C-terminus phosphorylation, which promotes beta-catenin transcriptional activity. beta-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 beta-catenin signaling, and ultimately influencing bone formation in response to intermittent PTH administration. |
