Gα_q signal in osteoblasts is inhibitory to the osteoanabolic action of parathyroid hormone

This study examined the role of the Gα_q signal constituted by Gα_q and Gα₁₁ (encoded by Gnα_q 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 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 Gnα₁₁ 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 Gnα₁₁ (Col1a1-Cre _+/-;Gna_q^fl/fl ;Gna₁₁^-/-) and found that the cDKO and single knock-out littermates of Gnα _q 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 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.