Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2009 Oct 23;4(10):e7583. doi: 10.1371/journal.pone.0007583.
Parathyroid hormone (PTH) is a potent anabolic agent for the treatment of osteoporosis. However, its mechanism of action in osteoblast and bone is not well understood. In this study, we show that the anabolic actions of PTH in bone are severely impaired in both growing and adult ovariectomized mice lacking bone-related activating transcription factor 4 (ATF4). Our study demonstrates that ATF4 deficiency suppresses PTH-stimulated osteoblast proliferation and survival and abolishes PTH-induced osteoblast differentiation, which, together, compromise the anabolic response. We further demonstrate that the PTH-dependent increase in osteoblast differentiation is correlated with ATF4-dependent up-regulation of Osterix. This regulation involves interactions of ATF4 with a specific enhancer sequence in the Osterix promoter. Furthermore, actions of PTH on Osterix require this same element and are associated with increased binding of ATF4 to chromatin. Taken together these experiments establish a fundamental role for ATF4 in the anabolic actions of PTH on the skeleton.
甲状旁腺激素 (PTH) 是一种有效的合成代谢药物，可用于治疗骨质疏松症。然而，其在成骨细胞和骨骼中的作用机制尚未完全阐明。在这项研究中，我们发现，在生长中和成年去卵巢的小鼠中，缺乏与骨相关的激活转录因子 4 (ATF4) 会严重损害 PTH 在骨骼中的合成代谢作用。我们的研究表明，ATF4 缺乏抑制了 PTH 刺激的成骨细胞增殖和存活，并消除了 PTH 诱导的成骨细胞分化，这共同影响了合成代谢反应。我们进一步证明，PTH 依赖性的成骨细胞分化增加与 ATF4 依赖性的 Osterix 上调有关。这种调节涉及 ATF4 与 Osterix 启动子中特定增强子序列的相互作用。此外，PTH 对 Osterix 的作用需要这个相同的元件，并与 ATF4 与染色质的结合增加有关。这些实验共同确立了 ATF4 在 PTH 对骨骼的合成代谢作用中的基本作用。
