Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE 19716, USA.
Bone. 2013 May;54(1):68-75. doi: 10.1016/j.bone.2013.01.028. Epub 2013 Jan 26.
Intermittent PTH administration directly stimulates osteoblasts; however, mechanisms of bone accrual that are independent of the direct actions on osteoblasts may be under-appreciated. Our aims were to decipher (1) whether PTH 1-84 augments vasodilation of the femoral principal nutrient artery (PNA), (2) whether 15 days of intermittent PTH 1-84 augments endothelium-dependent and/or -independent vasodilation of the femoral PNA, and (3) the signaling mechanisms involved.
Experiment 1: Femoral PNAs from male Wistar rats were exposed to cumulative doses of PTH 1-84 with and without an anti-vascular endothelial growth factor antibody and/or the endothelial NO synthase inhibitor l-NAME. Experiment 2: Male Wistar rats were administered PTH and/or the anti-VEGF antibody for 2 weeks. Subsequently, endothelium-dependent vasodilation to acetylcholine and endothelium-independent vasodilation to sodium nitroprusside were assessed. In addition, endothelium-dependent signaling pathways were analyzed by use of l-NAME and/or and the cyclooxygenase inhibitor indomethacin.
Cumulative doses of PTH 1-84 induced vasodilation of the femoral PNA, which was reduced by 38% and 87% with the anti-VEGF antibody and l-NAME, respectively. Secondly, 2 weeks of intermittent PTH 1-84 administration doubled trabecular bone volume, augmented bone formation parameters and reduced osteoclast activity. In addition, PTH enhanced endothelium-dependent vasodilation via up-regulation of NO. Co-administration of the anti-VEGF antibody (1) inhibited the PTH-induced increase in bone volume and remodeling parameters and (2) blunted the augmented vasodilator responsiveness of the PNA. Finally, endothelium-dependent vasodilation in PTH-treated rats was highly correlated with trabecular bone volume.
As hypothesized, PTH enhanced endothelium-dependent vasodilation of the femoral PNA via augmented NO production and was mediated partially through VEGF signaling. Further, vasodilation to PTH appears independent of vascular smooth muscle cell participation. More importantly, the strong association between vasodilation and bone volume suggests that bone arteriolar function is critical for PTH-induced bone anabolism.
间歇性甲状旁腺素（PTH）的给药直接刺激成骨细胞；然而，可能还存在不依赖于成骨细胞的直接作用的骨量增加机制，目前尚未得到充分认识。我们的目的是：（1）阐明 PTH1-84 是否增强股骨主要营养动脉（PNA）的血管舒张作用；（2）阐明 15 天间歇性 PTH1-84 是否增强股骨 PNA 的内皮依赖性和/或非内皮依赖性血管舒张作用；（3）阐明涉及的信号转导机制。
实验 1：雄性 Wistar 大鼠的股骨 PNA 暴露于累积剂量的 PTH1-84 及同时存在血管内皮生长因子（VEGF）抗体和/或内皮型一氧化氮合酶抑制剂 l-NAME 的情况下，检测其血管舒张作用。实验 2：雄性 Wistar 大鼠接受 PTH 和/或 VEGF 抗体治疗 2 周。随后，评估乙酰胆碱诱导的内皮依赖性血管舒张作用和硝普钠诱导的内皮非依赖性血管舒张作用。此外，使用 l-NAME 和/或环氧化酶抑制剂吲哚美辛分析内皮依赖性信号通路。
累积剂量的 PTH1-84 诱导了股骨 PNA 的血管舒张作用，VEGF 抗体和 l-NAME 分别使该作用降低 38%和 87%。其次，2 周间歇性 PTH1-84 给药使小梁骨体积增加一倍，增加了骨形成参数并减少了破骨细胞活性。此外，PTH 通过上调一氧化氮（NO）来增强内皮依赖性血管舒张作用。VEGF 抗体的共同给药（1）抑制了 PTH 引起的骨体积和重塑参数的增加；（2）减弱了 PNA 的增强的血管舒张反应性。最后，在接受 PTH 治疗的大鼠中，内皮依赖性血管舒张作用与小梁骨体积高度相关。
正如假设的那样，PTH 通过增强 NO 的产生来增强股骨 PNA 的内皮依赖性血管舒张作用，该作用部分通过 VEGF 信号转导介导。此外，PTH 诱导的血管舒张作用似乎不依赖于血管平滑肌细胞的参与。更重要的是，血管舒张作用与骨体积之间的强相关性表明，骨小动脉功能对于 PTH 诱导的骨合成至关重要。
