Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone.
Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone.
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DOI：
10.1371/journal.pone.0007583
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发表时间：
2009-10-23
期刊：
影响因子：
3.7
通讯作者：
Xiao G
中科院分区：
文献类型：
--
作者：
Yu S;Franceschi RT;Luo M;Fan J;Jiang D;Cao H;Kwon TG;Lai Y;Zhang J;Patrene K;Hankenson K;Roodman GD;Xiao G
甲状旁腺激素（PTH）是治疗骨质疏松症的有效合成代谢剂。然而，其在成骨细胞和骨中的作用机制尚不清楚。在这项研究中，我们发现PTH在骨中的合成代谢作用在缺乏骨相关激活转录因子4 （ATF4）的生长和成年去卵巢小鼠中都严重受损。我们的研究表明，ATF4缺乏抑制甲状旁腺素刺激的成骨细胞增殖和存活，并消除甲状旁腺素诱导的成骨细胞分化，这两者共同损害了合成代谢反应。我们进一步证明，成骨细胞分化中pth依赖性的增加与Osterix中atf4依赖性的上调相关。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的作用需要相同的元件，并与ATF4与染色质的结合增加有关。综上所述，这些实验确定了ATF4在甲状旁腺激素对骨骼的合成代谢作用中的基本作用。
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.