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

This study examined the role of the G alpha(q) signal constituted by G alpha(q) and G alpha(11) (encoded by Gn alpha(q) and Gn alpha(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 Gn alpha(q) gene under the control of 2.3-kb type I collagen alpha 1 chain (Col1a1) promoter exhibited osteopenia with decreased bone formation parameters and did not respond to the daily PTH treatment. We then established osteoblast-specific Gn alpha(q) and Gn alpha(11) double-knock-out (cDKO) mice by crossing the 2.3-kb Col1a1 promoter-Cre recombinase transgenic mice and those with Gn alpha(q) gene flanked with loxP and global ablation of Gn alpha(11) (Col1a1-Cre(+/-);Gn alpha(fl/fl)(q);Gna(11)(-/-)) and found that the cDKO and single knock-out litterrnates of Gn alpha(q) or Gn alpha(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 G alpha(q) signal deficiency in a cell-autonomous mechanism, in association with the membrane translocation of protein kinase C delta. This enhancement was reproduced by oyerexpression of regulator of G protein signaling-2, a G alpha(q) signal inhibitor, in osteoblastic MC3T3-E1 cells. Hence, the G alpha(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.