Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor.
Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor.
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通过PTH受体下游的不同机制对机械负荷和PTH的响应控制骨变性。
DOI：
10.1002/jbmr.3011
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Bellido T
中科院分区：
文献类型：
--
作者：
Delgado-Calle J;Tu X;Pacheco-Costa R;McAndrews K;Edwards R;Pellegrini GG;Kuhlenschmidt K;Olivos N;Robling A;Peacock M;Plotkin LI;Bellido T
骨细胞通过鲜为人知的机制整合骨骼对机械刺激和激素刺激的反应。我们在这里报道，牙本质基质蛋白1(DMP1)-8KB表达细胞(CKO)中甲状旁腺激素(PTH)受体1(Pth1r)有条件缺失的小鼠表现出适度的骨吸收减少，导致松质骨轻微增加，而皮质骨没有变化。然而，在低钙饮食诱导的生长或成年CKO小鼠中，内源性PTH慢性升高所致的骨吸收仍然完好无损，因为骨重建和骨丢失的增加与对照组小鼠没有区别。与对照组相比，CKO组小鼠每日注射甲状旁腺素引起的松质骨和皮质骨的骨量增加和骨形成增加，以及尺骨轴向负荷引起的骨膜移位明显减少。然而，值得注意的是，每天注射甲状旁腺素的野生型对照小鼠和过度表达SOST的转基因小鼠表现出相似的Wnt/β-catenin信号激活，增加骨形成，以及松质骨和皮质骨的增加。综上所述，这些发现表明，表达DMP1-8KB的细胞中的Pth1r是维持骨吸收基础水平所必需的，但对于慢性甲状旁腺素升高的分解代谢作用是必不可少的；它对于每天注射甲状旁腺素和机械负荷的合成代谢作用是必不可少的。然而，以前被证明是机械负荷诱导的骨合成代谢所必需的Sost/skerostin的下调对于PTH诱导的骨生长并不是必需的，这表明在DMP1-8KB表达细胞中Pth1r下游的其他机制与激素效应有关。
Osteocytes integrate the responses of bone to mechanical and hormonal stimuli by poorly understood mechanisms. We report here that mice with conditional deletion of the parathyroid hormone (PTH) receptor 1 (Pth1r) in dentin matrix protein 1 (DMP1)-8kb–expressing cells (cKO) exhibit a modest decrease in bone resorption leading to a mild increase in cancellous bone without changes in cortical bone. However, bone resorption in response to endogenous chronic elevation of PTH in growing or adult cKO mice induced by a low calcium diet remained intact, because the increased bone remodeling and bone loss was indistinguishable from that exhibited by control littermates. In contrast, the bone gain and increased bone formation in cancellous and cortical bone induced by daily injections of PTH and the periosteal bone apposition induced by axial ulna loading were markedly reduced in cKO mice compared to controls. Remarkably, however, wild-type (WT) control littermates and transgenic mice overexpressing SOST injected daily with PTH exhibit similar activation of Wnt/β-catenin signaling, increased bone formation, and cancellous and cortical bone gain. Taken together, these findings demonstrate that Pth1r in DMP1-8kb–expressing cells is required to maintain basal levels of bone resorption but is dispensable for the catabolic action of chronic PTH elevation; and it is essential for the anabolic actions of daily PTH injections and mechanical loading. However, downregulation of Sost/sclerostin, previously shown to be required for bone anabolism induced by mechanical loading, is not required for PTH-induced bone gain, showing that other mechanisms downstream of the Pth1r in DMP1-8kb–expressing cells are responsible for the hormonal effect.
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