Lhx2 regulates bone remodeling in mice by modulating RANKL signaling in osteoclasts
Lhx2 regulates bone remodeling in mice by modulating RANKL signaling in osteoclasts
复制标题
DOI：
10.1038/cdd.2014.71
复制
发表时间：
2014-10-01
影响因子：
12.4
通讯作者：
Kim, N.
中科院分区：
文献类型：
--
作者：
Kim, J. H.;Youn, B. U.;Kim, N.
LIM 同源框 2 (Lhx2) 转录因子 Lhx2 具有多种功能，包括神经诱导、形态发生和造血功能。在这里，我们展示了 Lhx2 参与破骨细胞分化的过程。 Lhx2在破骨细胞前体细胞中强烈表达，但在核因子κB配体受体激活剂（RANKL）介导的破骨细胞生成过程中其表达显着降低。 Lhx2 在骨髓源性单核细胞/巨噬细胞谱系细胞 (BMM)（破骨细胞前体细胞）中过度表达，通过抑制活化 T 细胞 c1 (NFATc1) 核因子的诱导，减弱 RANKL 诱导的破骨细胞分化。有趣的是，Lhx2 蛋白与 c-Fos 的相互作用减弱了 c-Fos 的 DNA 结合能力，从而抑制了 NFATc1 的反式激活。此外，Lhx2条件敲除小鼠表现出骨质疏松骨表型，这与体内破骨细胞形成增加有关。综上所述，我们的结果表明 Lhx2 在体外和体内充当破骨细胞形成的负调节因子。 Lhx2 的抗破骨细胞作用可能有助于开发骨疾病的治疗策略。
The LIM homeobox 2 (Lhx2) transcription factor Lhx2 has a variety of functions, including neural induction, morphogenesis, and hematopoiesis. Here we show the involvement of Lhx2 in osteoclast differentiation. Lhx2 was strongly expressed in osteoclast precursor cells but its expression was significantly reduced during receptor activator of nuclear factor-kappa B ligand (RANKL)mediated osteoclastogenesis. Overexpression of Lhx2 in bone marrow-derived monocyte/macrophage lineage cells (BMMs), which are osteoclast precursor cells, attenuated RANKL-induced osteoclast differentiation by inhibiting the induction of nuclear factor of activated T cells c1 (NFATc1). Interestingly, interaction of Lhx2 proteins with c-Fos attenuated the DNA-binding ability of c-Fos and thereby inhibited the transactivation of NFATc1. Furthermore, Lhx2 conditional knockout mice exhibited an osteoporotic bone phenotype, which was related with increased osteoclast formation in vivo. Taken together, our results suggest that Lhx2 acts as a negative regulator of osteoclast formation in vitro and in vivo. The anti-osteoclastogenic effect of Lhx2 may be useful for developing a therapeutic strategy for bone disease.