N-cadherin restrains PTH activation of Lrp6/β-catenin signaling and osteoanabolic action

Leila Revollo, Jacqueline Kading, Sung Yeop Jeong, Jiemin Li, Valerie Salazar, Gabriel Mbalaviele, Roberto Civitelli

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish
Pages (from-to)274-285
Number of pages12
JournalJournal of Bone and Mineral Research
Volume30
Issue number2
DOIs
StatePublished - Feb 1 2015

Keywords

  • B-catenin
  • Cadherins
  • Lrp6
  • PKA
  • Parathyriod hormone

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