Abstract：
The maternal skeleton experiences significant bone loss during lactation, followed by rapid restoration post weaning. Parathyroid-related protein (PTHrP)-induced acidification of the perilacunar matrix by osteocytes is crucial in this process, yet its mechanism remains unclear. Here, we identify Cx43 hemichannels (HCs) as key mediators of osteocyte acidification and perilacunar-canalicular remodeling (PLR). Utilizing transgenic mouse models expressing dominant-negative Cx43 mutants, we show that mice with impaired Cx43 HCs exhibit attenuated lactation-induced responses compared to wild-type and only gap junction-impaired groups, including lacunar enlargement, upregulation of PLR genes, and bone loss with compromised mechanical properties. Furthermore, inhibition of HCs by a Cx43 antibody blunts PTHrP-induced calcium influx and protein kinase A activation, followed by impaired osteocyte acidification. Additionally, impeded HCs suppress bone recovery during the post-lactation period. Our findings highlight the pivotal role of Cx43 HCs in orchestrating dynamic bone changes during lactation and recovery by regulating acidification and remodeling enzyme expression.
摘要：
产妇骨骼在哺乳期间经历显著的骨丢失,其次是断奶后快速恢复。甲状旁腺相关蛋白（PTHrP）诱导的骨细胞对周围基质的酸化在此过程中至关重要，但其机制尚不清楚。这里,我们确定Cx43半通道(HCs)是骨细胞酸化和髓-小管重建(PLR)的关键介质.利用表达显性阴性Cx43突变体的转基因小鼠模型，我们显示，与野生型和仅间隙连接受损组相比，Cx43HCs受损的小鼠表现出减弱的泌乳诱导反应。包括腔隙扩大,PLR基因的上调，和力学性能受损的骨质流失。此外，Cx43抗体对HC的抑制作用减弱了PTHrP诱导的钙内流和蛋白激酶A的激活，其次是骨细胞酸化受损。此外,受阻碍的HC抑制泌乳后的骨恢复。我们的发现强调了Cx43HCs在通过调节酸化和重塑酶表达来协调泌乳和恢复过程中动态骨骼变化中的关键作用。
