Gαq Signal in Osteoblasts Is Inhibitory to the Osteoanabolic Action of Parathyroid Hormone

This study examined the role of the Gαq signal constituted by Gαq and Gα11 (encoded by Gnαq and Gnα11, 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 Gnαq 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 Gnαq and Gnα11 double-knock-out (cDKO) mice by crossing the 2.3-kb Col1a1 promoter-Cre recombinase transgenic mice and those with Gnαq gene flanked with loxP and global ablation of Gnα11 (Col1a1-Cre+/−;Gnaqfl/fl;Gna11−/−) and found that the cDKO and single knock-out littermates of Gnαq or Gnα11 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 Gαq 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 Gαq signal inhibitor, in osteoblastic MC3T3-E1 cells. Hence, the Gαq 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.