title: N-cadherin restrains PTH activation of Lrp6/β-catenin signaling and osteoanabolic action.
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.
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Disease, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Revollo
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Kading
authors.forename: Sung Yeop
authors.initials: SY
authors.lastname: Jeong
authors.forename: Jiemin
authors.initials: J
authors.lastname: Li
authors.forename: Valerie
authors.initials: V
authors.lastname: Salazar
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mbalaviele
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000076182:Sp7 Transcription Factor; D051820:TCF Transcription Factors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D045930:Anabolic Agents; D015820:Cadherins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin
keywords: CADHERINS; LRP6; PARATHYROID HORMONE; PKA; Β-CATENIN
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