| RRC ID |
18206
|
| 著者 |
Ogata N, Shinoda Y, Wettschureck N, Offermanns S, Takeda S, Nakamura K, Segre GV, Chung UI, Kawaguchi H.
|
| タイトル |
G alpha(q) signal in osteoblasts is inhibitory to the osteoanabolic action of parathyroid hormone.
|
| ジャーナル |
J Biol Chem
|
| 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.
|
| 巻・号 |
286(15)
|
| ページ |
13733-40
|
| 公開日 |
2011-4-15
|
| DOI |
10.1074/jbc.M110.200196
|
| PII |
S0021-9258(20)51752-3
|
| PMID |
21345793
|
| PMC |
PMC3075717
|
| MeSH |
Animals
Bone and Bones / metabolism*
Bone and Bones / pathology
Cell Line
Crosses, Genetic
GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
Mice
Mice, Knockout
Organ Size / genetics
Osteoblasts / metabolism*
Osteoblasts / pathology
Osteoporosis / drug therapy
Osteoporosis / genetics
Osteoporosis / metabolism*
Parathyroid Hormone / pharmacology*
Protein Kinase C-delta
|
| IF |
4.238
|
| 引用数 |
16
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
MC3T3-E1(RCB1126) |
