Gα_S is a heterotrimeric G protein that transduces signals from cell surface G proteincoupled receptors to stimulate intracellular signaling cascades. Clinically, tight regulation of Gα_S levels and activity are required for bone homeostasis and aberrant Gα_S activity is known to cause various bone disorders. Our lab has previously found a 6-fold variation in Gα_S protein levels in lymphocytes from children, suggesting significant variability in cellular Gα_S levels amongst individuals. To examine the effects of increased Gα_S expression on bone in vivo, our lab has generated a transgenic mouse model of osteoblastic Gα_S overexpression (HOM-Gs mice) driven by the 3.6 kb Col1a1 promoter.

HOM-Gs mice demonstrated increased trabecular bone mass compared to wild type (WT) mice. Furthermore, HOM-Gs cortical bone was porous and mechanically weak. This skeletal phenotype showed a pronounced progression with age. Continual accrual of trabecular bone occurred in HOM-Gs mice, whereas a loss of bone was observed in WT mice. Histologically, these changes in skeletal morphology were shown to be mediated by increased bone turnover. At the cellular level, HOM-Gs mice exhibited overactive osteoblasts resulting in increased bone formation and increased resorption through enhanced osteoclastogenesis.

In response to anabolic (intermittent) parathyroid hormone (PTH) treatment, HOM-Gs mice displayed enhanced increases in trabecular bone mass compared to WT mice. Moreover, HOM-Gs mice demonstrated robust anabolic effects in trabecular bone from treadmill exercise when WT mice did not respond. Interestingly, HOM-Gs mice responded catabolically, similar to WT mice, to low calcium diet, but were resistant to the catabolic effects of continuous PTH. Collectively, these results suggest that stimulation of Gα_S signaling in the presence of additional Gα_S protein drives bone anabolism when sufficient calcium levels are present. Despite the increases in bone mass however, no biomechanical improvements were observed, indicating that bone formation was favored at the cost of bone quality.