title: N-cadherin restrains PTH repressive effects on sclerostin/SOST by regulating LRP6-PTH1R interaction.
abstract: 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; Cdh2f/f(Cdh2ΔDmp1) mice, compared with Cdh2f/fmice. Additionally, iPTH had greater bone anabolic effects in Cdh2ΔDmp1mice compared to Cdh2f/fmice. 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.
authors.affiliation: Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.|Department of Orthopaedics, People's Hospital of Jieshou City, Jieshou, Anhui, P.R. China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Hanfeng
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015820:Cadherins / Q000494:pharmacology*; D002478:Cells, Cultured; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; C489083:Cdh2 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; C473449:PTH1R protein, human; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; C486030:Sost protein, mouse
keywords: LRP6; N-cadherin; PTH; SOST; osteoblasts; osteocytes