Wang Liping, Wattanachanya Lalita, Piprode Vikrant, Nissenson Robert A
Endocrine Research Unit, VA Medical Center, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, CA, USA.
Calcif Tissue Int. 2025 Jul 16;116(1):98. doi: 10.1007/s00223-025-01409-2.
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.
间歇性给予甲状旁腺激素（PTH）可对骨骼产生强大的合成代谢作用。这些合成代谢作用似乎是由成骨细胞谱系细胞中PTH1受体（PTHR1）启动的Gs-环磷酸腺苷（cAMP）系统的激活介导的。Gs介导的cAMP生成可被Gi信号的激活所抑制，并且我们之前已经证明，成骨细胞中的Gi信号抑制骨形成，从而在雌性小鼠与衰老相关的骨质流失中起重要作用。目前尚不清楚随着衰老而增加的Gi信号是否会减弱对间歇性PTH（iPTH）给药的合成代谢反应。为了解决这种可能性，我们确定了在4月龄雌性小鼠中，成骨细胞中Gi信号的诱导性阻断对PTH合成代谢反应的影响。通过四环素调控由Col1(2.3)启动子驱动的百日咳毒素（PTX）的表达来实现Gi信号的阻断。我们发现，PTX的表达增强了iPTH对股骨远端和L4腰椎小梁骨的合成代谢作用。此外，PTH促进皮质骨厚度和强度的能力仅在表达PTX的小鼠中明显。这些新结果表明，成骨细胞中的内源性Gi信号限制了iPTH对成年雌性小鼠骨骼的合成代谢作用。抑制成骨细胞Gi信号的策略可为iPTH治疗绝经后骨质疏松症提供有效的辅助治疗。
