Amphiregulin is a novel growth factor involved in normal bone development and in the cellular response to parathyroid hormone stimulation
Amphiregulin is a novel growth factor involved in normal bone development and in the cellular response to parathyroid hormone stimulation
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DOI：
10.1074/jbc.m409807200
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发表时间：
2005-02-04
影响因子：
4.8
通讯作者：
Partridge, NC
中科院分区：
文献类型：
--
作者：
Qin, L;Tamasi, J;Partridge, NC
甲状旁腺激素（PTH）是钙稳态和骨重塑的主要介质，目前已知是治疗骨质疏松症的有效药物。然而，其在骨骼中发挥作用的机制在很大程度上尚不清楚。在这里，我们报道了表皮生长因子 (EGF) 家族成员双调蛋白 (AR) 的表达在几种成骨细胞系和骨组织中被 PTH 快速且高度上调。其他成骨激素（1α、25二羟基维生素 D-3 和前列腺素 E-2）也强烈刺激 AR 表达。我们发现所有EGF样配体及其受体均在成骨细胞中表达，但AR是唯一受PTH高度调控的成员。功能研究表明，虽然 AR 是前成骨细胞的有效生长因子，但它完全抑制进一步分化。 AR 还以 EGF 受体依赖性方式强烈且快速地刺激 Akt 和 ERK 磷酸化以及 c-fos 和 c-jun 表达。此外，AR缺失小鼠的胫骨小梁骨明显少于野生型小鼠。综上所述，我们发现了一种受 PTH 调节的新型生长因子，并且似乎在骨代谢中具有重要作用。
Parathyroid hormone (PTH) is the Major mediator of calcium homeostasis and bone remodeling and is now known to be an effective drug for osteoporosis treatment. Yet the mechanisms responsible for its functions in bone are largely unknown. Here we report that the expression of amphiregulin (AR), a member of the epidermal growth factor (EGF) family, is rapidly and highly up-regulated by PTH in several osteohlastic cell lines and bone tissues. Other osteotropic hormones (1alpha,25dihydroxyvitamin D-3 and prostaglandin E-2) also strongly stimulate AR expression. We found all EGF-like ligands and their receptors are expressed in osteoblasts, but AR is the only member that is highly regulated by PTH. Functional studies demonstrated that although AR is a potent growth factor for preosteoblasts, it completely inhibits further differentiation. AR also strongly and quickly stimulated Akt and ERK phosphorylation and c-fos and c-jun expression in an EGF receptor-dependent manner. Moreover, AR null mice displayed significantly less tibial trabecular bone than wild-type mice. Taken together, we have identified a novel growth factor that is PTH-regulated and appears to have an important role in bone metabolism.