Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan.
Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2561-6. doi: 10.1073/pnas.1116042109. Epub 2012 Jan 30.
Cell fate determination is tightly regulated by transcriptional activators and repressors. Leukemia/lymphoma-related factor (LRF; encoded by Zbtb7a), known as a POK (POZ/BTB and Krüppel) family transcriptional repressor, is induced during the development of bone-resorbing osteoclasts, but the physiological significance of LRF in bone metabolism and the molecular mechanisms underlying the transcriptional regulation of osteoclastogenesis by LRF have not been elucidated. Here we show that LRF negatively regulates osteoclast differentiation by repressing nuclear factor of activated T cells c1 (NFATc1) induction in the early phase of osteoclast development, while positively regulating osteoclast-specific genes by functioning as a coactivator of NFATc1 in the bone resorption phase. The stage-specific distinct functions of LRF were demonstrated in two lines of conditional knockout mice in which LRF was deleted in the early or late phase of osteoclast development. Thus, this study shows that LRF plays stage-specific distinct roles in osteoclast differentiation, exemplifying the delicate transcriptional regulation at work in lineage commitment.
细胞命运的决定受到转录激活因子和抑制因子的严密调控。白血病/淋巴瘤相关因子（LRF；由 Zbtb7a 编码），作为一个 POZ/BTB 和 Krüppel 家族转录抑制因子，在破骨细胞的骨吸收发育过程中被诱导，但 LRF 在骨代谢中的生理意义以及 LRF 对破骨细胞发生的转录调控的分子机制尚未阐明。在这里，我们表明 LRF 通过抑制核因子活化 T 细胞 c1（NFATc1）在破骨细胞发育的早期诱导来负调控破骨细胞分化，而在骨吸收阶段通过作为 NFATc1 的共激活因子来正调控破骨细胞特异性基因。在两条条件性敲除小鼠系中，LRF 在破骨细胞发育的早期或晚期被删除，证明了 LRF 的阶段特异性的不同功能。因此，这项研究表明，LRF 在破骨细胞分化中发挥阶段特异性的不同作用，体现了谱系决定中精细的转录调控。
