ATF3 controls proliferation of osteoclast precursor and bone remodeling.
ATF3 controls proliferation of osteoclast precursor and bone remodeling.
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DOI：
10.1038/srep30918
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发表时间：
2016-08-02
影响因子：
4.6
通讯作者：
Hinoi E
中科院分区：
文献类型：
--
作者：
Fukasawa K;Park G;Iezaki T;Horie T;Kanayama T;Ozaki K;Onishi Y;Takahata Y;Yoneda Y;Takarada T;Kitajima S;Vacher J;Hinoi E
骨稳态是通过骨吸收破骨细胞和骨形成成骨细胞的复杂耦合作用来维持的。在这里，我们确定激活转录因子3（ATF 3）作为一个关键的转录因子调节骨吸收和骨重建的病理条件下，通过调节破骨细胞前体细胞的增殖。破骨细胞特异性缺失ATF 3可预防核因子-κB受体激活因子配体（RANKL）诱导的骨吸收和骨丢失，尽管在生理条件下，这些敲除小鼠的骨体积和骨密度参数均未发生显著变化。RANKL依赖性破骨细胞生成在体外ATF 3缺失的骨髓巨噬细胞（BMM）中受损。从机制上讲，ATF 3的缺乏削弱了RANKL诱导的体内骨髓破骨细胞前体细胞增殖以及体外BMM细胞增殖的短暂增加。此外，ATF 3通过调节破骨细胞前体中激活蛋白-1依赖的转录来调节细胞周期蛋白D1 mRNA的表达，并且细胞周期蛋白D1的引入显著地挽救了ATF 3缺失的BMM中破骨细胞生成的损伤。因此，这些研究结果表明，ATF 3可能通过调节病理条件下的细胞增殖，在破骨细胞生成和骨稳态中发挥关键作用，从而为骨疾病提供靶点。
Bone homeostasis is maintained by the sophisticated coupled actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here we identify activating transcription factor 3 (ATF3) as a pivotal transcription factor for the regulation of bone resorption and bone remodeling under a pathological condition through modulating the proliferation of osteoclast precursors. The osteoclast precursor-specific deletion of ATF3 in mice led to the prevention of receptor activator of nuclear factor-κB (RANK) ligand (RANKL)-induced bone resorption and bone loss, although neither bone volume nor osteoclastic parameter were markedly altered in these knockout mice under the physiological condition. RANKL-dependent osteoclastogenesis was impaired in vitro in ATF3-deleted bone marrow macrophages (BMM). Mechanistically, the deficiency of ATF3 impaired the RANKL-induced transient increase in cell proliferation of osteoclast precursors in bone marrow in vivo as well as of BMM in vitro. Moreover, ATF3 regulated cyclin D1 mRNA expression though modulating activator protein-1-dependent transcription in the osteoclast precursor, and the introduction of cyclin D1 significantly rescued the impairment of osteoclastogenesis in ATF3-deleted BMM. Therefore, these findings suggest that ATF3 could have a pivotal role in osteoclastogenesis and bone homeostasis though modulating cell proliferation under pathological conditions, thereby providing a target for bone diseases.