N‐cadherin restrains PTH repressive effects on sclerostin/SOST by regulating LRP6–PTH1R interaction

Sclerostin/SOST is a robust negative regulator of bone formation. Loss‐of‐function mutations of the sclerostin gene ( SOST ) cause sclerosteosis and Van Buchem disease characterized by bone overgrowth. Mediated by myocyte enhancer factor 2 (MEF2) transcription factors, parathyroid hormone (PTH) suppresses SOST expression through formation of complexes of parathyroid hormone–parathyroid hormone‐related peptide receptor 1 (PTH1R) and lipoprotein receptor–related protein 6 (LRP6). N‐cadherin has been shown to negatively regulate Wnt/β‐catenin and PTH induced, protein kinase‐dependent β‐catenin signaling. Here, we investigated whether N‐cadherin mediates the inhibitory effects of PTH on sclerostin/SOST. In vitro , overexpression of N‐cadherin resulted in blunted PTH suppressive effects on sclerostin/SOST expression, as detected by immunoblot and qPCR analysis; PTH‐induced downregulation of MEF2A, C, and D was impaired by N‐cadherin; and N‐cadherin reduced LRP6–PTHR1 interaction and endocytosis in response to PTH. In vivo , intermittent PTH (iPTH)–induced suppression of sclerostin/SOST was accentuated in Dmp1‐cre ; Cdh2 f/f ( Cdh2 ΔDmp1 ) mice, compared with Cdh2 f/f mice. Additionally, iPTH had greater bone anabolic effects in Cdh2 ΔDmp1 mice compared to Cdh2 f/f mice. These data indicate that N‐cadherin negatively mediates PTH suppressive effects on sclerostin/SOST by regulating LRP6–PTHR1 interaction, ultimately influencing PTH anabolic effects on bone.