Gli1 Protein Participates in Hedgehog-mediated Specification of Osteoblast Lineage during Endochondral Ossification
Gli1 Protein Participates in Hedgehog-mediated Specification of Osteoblast Lineage during Endochondral Ossification
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DOI：
10.1074/jbc.m112.347716
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发表时间：
2012-05-18
影响因子：
4.8
通讯作者：
Chung, Ung-il
中科院分区：
文献类型：
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作者：
Hojo, Hironori;Ohba, Shinsuke;Chung, Ung-il
关于哺乳动物发育中的Hedgehog信号，大多数研究都集中在Gli 2和Gli 3而不是Gli 1上。这是因为Gli 1（-/-）小鼠在成年期没有表现出任何大体异常，并且没有对胎儿Gli 1（-/-）小鼠的详细分析。在这项研究中，我们研究了Gli 1在成骨中的生理作用。组织学分析显示，与WT胎仔相比，Gli 1（-/-）胎仔的骨形成受损。Gli 1（-/-）软骨膜细胞既不表达runx相关转录因子2（Runx 2），也不表达osterix，成骨的主要调节因子，与WT细胞相反。体外分析表明，Gli 1的过表达上调WT和Runx 2（-/-）软骨膜细胞中的早期成骨相关基因，Gli 1通过与其5 '调控区的结合激活这些基因的转录，这是Gli 1在软骨膜中功能的基础。此外，Gli 1（-/-）; Gli 2（-/-）小鼠表现出比Gli 1（-/-）或Gli 2（-/-）小鼠更严重的骨形成受损表型，并且与Gli 3（-/-）细胞相比，Gli 1（-/-）; Gli 3（-/-）软骨膜细胞中的成骨细胞分化受损。这些数据表明，Gli 1本身可以诱导早期成骨细胞分化，至少在一定程度上，在Runx 2独立的方式。它还与Gli 2起着冗余的作用，并参与骨生成中Gli 3的阻遏物功能。基于这些发现，我们提出，在刺猬输入，Gli 1功能集体与Gli 2和Gli 3在成骨。
With regard to Hedgehog signaling in mammalian development, the majority of research has focused on Gli2 and Gli3 rather than Gli1. This is because Gli1(-/-) mice do not show any gross abnormalities in adulthood, and no detailed analyses of fetal Gli1(-/-) mice are available. In this study, we investigated the physiological role of Gli1 in osteogenesis. Histological analyses revealed that bone formation was impaired in Gli1(-/-) fetuses compared with WT fetuses. Gli1(-/-) perichondrial cells expressed neither runt-related transcription factor 2 (Runx2) nor osterix, master regulators of osteogenesis, in contrast to WT cells. In vitro analyses showed that overexpression of Gli1 up-regulated early osteogenesis-related genes in both WT and Runx2(-/-) perichondrial cells, and Gli1 activated transcription of those genes via its association with their 5'-regulatory regions, underlying the function of Gli1 in the perichondrium. Moreover, Gli1(-/-);Gli2(-/-) mice showed more severe phenotypes of impaired bone formation than either Gli1(-/-) or Gli2(-/-) mice, and osteoblast differentiation was impaired in Gli1(-/-);Gli3(-/-) perichondrial cells compared with Gli3(-/-) cells in vitro. These data suggest that Gli1 itself can induce early osteoblast differentiation, at least to some extent, in a Runx2-independent manner. It also plays a redundant role with Gli2 and is involved in the repressor function of Gli3 in osteogenesis. On the basis of these findings, we propose that upon Hedgehog input, Gli1 functions collectively with Gli2 and Gli3 in osteogenesis.