title: G alpha(q) signal in osteoblasts is inhibitory to the osteoanabolic action of parathyroid hormone.
abstract: This study examined the role of the Gα(q) signal constituted by Gα(q) and Gα(11) (encoded by Gnα(q) and Gnα(11), respectively), a major intracellular pathway of parathyroid hormone (PTH), in the PTH osteoanabolic action by the gain- and loss-of-function analyses. Transgenic mice with osteoblast-specific overexpression of the constitutively active Gnα(q) gene under the control of 2.3-kb type I collagen α1 chain (Col1a1) promoter exhibited osteopenia with decreased bone formation parameters and did not respond to the daily PTH treatment. We then established osteoblast-specific Gnα(q) and Gnα(11) double-knock-out (cDKO) mice by crossing the 2.3-kb Col1a1 promoter-Cre recombinase transgenic mice and those with Gnα(q) gene flanked with loxP and global ablation of Gnα(11) (Col1a1-Cre(+/-);Gna(q)(fl/fl);Gna(11)(-/-)) and found that the cDKO and single knock-out littermates of Gnα(q) or Gnα(11) exhibited normal bone volume and turnover under physiological conditions. With a daily injection of PTH, however, the cDKO mice, but not the single knock-out mice, showed higher bone volume and turnover than the wild-type littermates. Cultures of primary osteoblasts derived from cDKO and wild-type littermates confirmed enhancement of the PTH osteoanabolic action by the Gα(q) signal deficiency in a cell-autonomous mechanism, in association with the membrane translocation of protein kinase Cδ. This enhancement was reproduced by overexpression of regulator of G protein signaling-2, a Gα(q) signal inhibitor, in osteoblastic MC3T3-E1 cells. Hence, the Gα(q) signal plays an inhibitory role in the PTH osteoanabolic action, suggesting that its suppression may lead to a novel treatment in combination with PTH against osteoporosis.
authors.affiliation: Department of Bone and Cartilage Regenerative Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Ogata
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Gino V
authors.initials: GV
authors.lastname: Segre
authors.forename: Ung-il
authors.initials: UI
authors.lastname: Chung
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D003433:Crosses, Genetic; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D051745:Protein Kinase C-delta
chemical_list: D010281:Parathyroid Hormone; D051745:Protein Kinase C-delta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11