title: Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy.
abstract: Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsα in the osteoblast lineage. Postnatal removal of Gsα in the osteoblast lineage (P-Gsα(OsxKO) mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1-34) (80 μg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-Gsα(OsxKO) mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-Gsα(OsxKO) mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsα but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsα and Gq/11 act downstream of PTH on osteoblast differentiation.
authors.affiliation: From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Partha
authors.initials: P
authors.lastname: Sinha
authors.affiliation: From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114,; Department of Clinical Chemistry, University of Helsinki and Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Laboratory Services, HUSLAB, 00029 HUS, Finland.
authors.forename: Piia
authors.initials: P
authors.lastname: Aarnisalo
authors.affiliation: From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Chubb
authors.affiliation: St. Vincent's Institute and Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Poulton
authors.affiliation: From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Gregory
authors.initials: G
authors.lastname: Nachtrab
authors.affiliation: Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Swami
authors.affiliation: Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Hamid
authors.initials: H
authors.lastname: Saeed
authors.affiliation: Metabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Metabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.affiliation: Departments of Orthopedic Surgery and Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Ernestina
authors.initials: E
authors.lastname: Schipani
authors.affiliation: St. Vincent's Institute and Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.affiliation: From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.affiliation: From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114,; Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305,. Electronic address: jywu1@stanford.edu.
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Wu
mesh_terms: D045930:Anabolic Agents / Q000008:administration & dosage*; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency* / Q000235:genetics; D020249:Hormone Replacement Therapy; D006801:Humans; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000008:administration & dosage*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D045930:Anabolic Agents; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: G protein; G protein-coupled receptor (GPCR); PTH/PTH-related peptide receptor; osteoblast; osteoporosis; parathyroid hormone