Blockade of Gi Signaling Enhances the Anabolic Effect of Parathyroid Hormone in Female Mice.

Abstract

Intermittent administration of parathyroid hormone (PTH) produces potent anabolic effects on bone. These anabolic effects appear to be mediated by activation of the Gs-cyclic AMP system initiated by the PTH1 receptor (PTHR1) in osteoblast lineage cells. Gs-mediated cyclic AMP production can be inhibited by activation of Gi signaling, and we have previously demonstrated that Gi signaling in osteoblasts suppresses bone formation and thereby plays a prominent role in the bone loss associated with aging in female mice. It is not clear whether this increased Gi signaling with aging dampens the anabolic response to intermittent PTH (iPTH) administration. To address this possibility, we determined the effect of inducible blockade of Gi signaling in osteoblasts on the anabolic response to PTH in 4-month-old female mice. Blockade of Gi signaling was achieved by tetracycline-regulated expression of pertussis toxin (PTX) driven by a Col1(2.3) promoter. We found that the expression of PTX potentiated the anabolic effect of iPTH on the trabecular bone, both at the distal femur and L4 lumbar vertebra. In addition, the ability of PTH to promote cortical bone thickness and strength was evident only in mice expressing PTX. These novel results demonstrate that endogenous Gi signaling in osteoblasts limits the anabolic action of iPTH on the skeleton of adult female mice. Strategies that suppress osteoblast Gi signaling could provide an effective adjunct to iPTH therapy in the treatment of postmenopausal osteoporosis.