Das Amitabh, Wang Xiaobei, Kang Jessica, Coulter Alyssa, Shetty Amol C, Bachu Mahesh, Brooks Stephen R, Dell'Orso Stefania, Foster Brian L, Fan Xiaoxuan, Ozato Keiko, Somerman Martha J, Thumbigere-Math Vivek
Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA.
Laboratory of Oral and Connective Tissue Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, MD, USA.
J Bone Miner Res. 2021 Jan;36(1):199-214. doi: 10.1002/jbmr.4165. Epub 2020 Sep 11.
Osteoclasts (OCs) are bone-resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild-type (WT) mice, Ly6C and Ly6C monocytes are the primary source of OC formation when compared to Ly6C monocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of preestablished transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of interferon regulatory factor 8 (IRF8), a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis in Irf8-deficient mice. Collectively, our study provides novel insights into the transcription factors and active cis-regulatory elements that regulate OC differentiation. © 2020 American Society for Bone and Mineral Research (ASBMR).
破骨细胞（OCs）是由单核细胞连续融合形成的骨吸收细胞。在小鼠和人类中，存在三种不同的单核细胞亚群；然而，尚不清楚它们是否都具有破骨细胞生成潜能。在此我们表明，在野生型（WT）小鼠中，与Ly6C⁻单核细胞相比，Ly6C⁺和Ly6C⁻单核细胞是OC形成的主要来源。它们的破骨细胞生成潜能由信号受体表达增加、既定转录本的激活以及增强子活性的从头增加和启动子变化所决定。在缺乏对骨髓生成和破骨细胞生成很重要的转录因子干扰素调节因子8（IRF8）的情况下，所有三个单核细胞亚群都被编程为显示出更高的破骨细胞生成潜能。增强的NFATc1核转位以及在早期发育阶段开始的转录组和表观遗传变化的放大，指导了Irf8缺陷小鼠中破骨细胞生成的增加。总体而言，我们的研究为调节OC分化的转录因子和活性顺式调节元件提供了新的见解。©2020美国骨与矿物质研究学会（ASBMR）。
