1. Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling
- Author
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Maureen J O'Meara, Daniel J. Brooks, Janaina S. Martins, Ugur M. Ayturk, Hiroshi Noda, Rebecca Berdeaux, Wanida Ono, Marc Foretz, Christopher J Janton, Christian D. Castro, Marc N. Wein, Mizuki Nagata, Thomas J. Gardella, Shigeki Nishimori, Ruslan I. Sadreyev, Henry M. Kronenberg, Harald Jüppner, Mary L. Bouxsein, Murat Cetinbas, Michael Bruce, Instituto Nacional de Pesquisas da Amazônia (INPA), University of Adelaide, Orthopedic Biomechanics Laboratory (BIDMC), Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Endocrine Unit, Massachusetts General Hospital [Boston], Beth Israel Deaconess Medical Center [Boston] (BIDMC)-Harvard Medical School [Boston] (HMS), Endocrine Unit, Department of Medicine, and Pediatric Neprology Unit, and MassGeneral Hospital for Children
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Male ,0301 basic medicine ,Bone disease ,Parathyroid hormone ,Mice ,0302 clinical medicine ,Endocrinology ,Bone cell ,Phosphorylation ,Receptor ,Mice, Knockout ,Extracellular Matrix Proteins ,Kinase ,Bone development ,General Medicine ,Protein-Tyrosine Kinases ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Phenotype ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Cell biology ,Histone ,Parathyroid Hormone ,030220 oncology & carcinogenesis ,Bone Biology ,Bone Remodeling ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,Protein Serine-Threonine Kinases ,Biology ,Osteocytes ,03 medical and health sciences ,Chondrocytes ,medicine ,Animals ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Cell Proliferation ,Receptor, Parathyroid Hormone, Type 1 ,G protein-coupled receptor ,Osteoblasts ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Hypertrophy ,medicine.disease ,Osteoclast/osteoblast biology ,030104 developmental biology ,Animals, Newborn ,Mutation ,biology.protein ,Transcriptome ,Gene Deletion - Abstract
International audience; The parathyroid hormone 1 receptor (PTH1R) mediates the biologic actions of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). Here, we showed that salt-inducible kinases (SIKs) are key kinases that control the skeletal actions downstream of PTH1R and that this GPCR, when activated, inhibited cellular SIK activity. Sik gene deletion led to phenotypic changes that were remarkably similar to models of increased PTH1R signaling. In growth plate chondrocytes, PTHrP inhibited SIK3, and ablation of this kinase in proliferating chondrocytes rescued perinatal lethality of PTHrP-null mice. Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen's metaphyseal chondrodysplasia. Finally, genetic evidence demonstrated that class IIa histone deacetylases were key PTH1R-regulated SIK substrates in both chondrocytes and osteocytes. Taken together, our findings establish that SIK inhibition is central to PTH1R action in bone development and remodeling. Furthermore, this work highlights the key role of cAMP-regulated SIKs downstream of GPCR action.
- Published
- 2019
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