Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription
Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription
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DOI：
10.1242/dev.043281
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发表时间：
2009-12-15
期刊：
影响因子：
4.6
通讯作者：
Yang, Xiangli
中科院分区：
文献类型：
--
作者：
Wang, Weiguang;Lian, Na;Yang, Xiangli
激活转录因子 4 (Atf4) 是 cAMP 反应元件结合蛋白 (CREB) 家族中一种含有亮氨酸拉链的蛋白。小鼠中 Atf4 (Atf4(-/-)) 的消融会导致严重的骨骼缺陷，包括延迟骨化和低骨量、身材矮小和四肢短小。 Atf4 在增殖和肥大前生长板软骨细胞中表达，表明 Atf4 在软骨内骨化过程中在软骨细胞中具有自主功能。在Atf4(-/-)生长板中，增殖软骨细胞的典型柱状结构被扰乱。增殖区缩短，而肥大区短暂扩大。印度刺猬蛋白（Ihh）的表达显着降低，而其他软骨细胞标志基因，如II型胶原蛋白（Col2a1）、PTH/PTHrP受体（Pth1r）和X型胶原蛋白（Col10a1）的表达正常。此外，软骨细胞中Atf4的强制表达会诱导内源性Ihh mRNA，Atf4直接与Ihh启动子结合并激活其转录。支持这些发现的是，在小鼠肢体外植体中重新激活 Hh 信号传导可纠正 Atf4(-/-) 软骨细胞增殖和短肢表型。因此，这项研究将 Atf4 确定为软骨细胞中 Ihh 的新型转录激活剂，通过控制生长板软骨细胞增殖和分化来调节纵向骨生长。
Activating transcription factor 4 (Atf4) is a leucine-zipper-containing protein of the cAMP response element-binding protein (CREB) family. Ablation of Atf4 (Atf4(-/-)) in mice leads to severe skeletal defects, including delayed ossification and low bone mass, short stature and short limbs. Atf4 is expressed in proliferative and prehypertrophic growth plate chondrocytes, suggesting an autonomous function of Atf4 in chondrocytes during endochondral ossification. In Atf4(-/-) growth plate, the typical columnar structure of proliferative chondrocytes is disturbed. The proliferative zone is shortened, whereas the hypertrophic zone is transiently expanded. The expression of Indian hedgehog (Ihh) is markedly decreased, whereas the expression of other chondrocyte marker genes, such as type II collagen (Col2a1), PTH/PTHrP receptor (Pth1r) and type X collagen (Col10a1), is normal. Furthermore, forced expression of Atf4 in chondrocytes induces endogenous Ihh mRNA, and Atf4 directly binds to the Ihh promoter and activates its transcription. Supporting these findings, reactivation of Hh signaling pharmacologically in mouse limb explants corrects the Atf4(-/-) chondrocyte proliferation and short limb phenotypes. This study thus identifies Atf4 as a novel transcriptional activator of Ihh in chondrocytes that paces longitudinal bone growth by controlling growth plate chondrocyte proliferation and differentiation.