Monocyte Subsets With High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8.
Amitabh DasXiaobei WangJessica KangAlyssa CoulterAmol C ShettyMahesh BachuStephen R BrooksStefania Dell'OrsoBrian L FosterXiaoxuan FanKeiko OzatoMartha J SomermanVivek Thumbigere-MathPublished in: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (2020)
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, Ly6Chi and Ly6Cint 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).
Keyphrases
- transcription factor
- dendritic cells
- peripheral blood
- wild type
- bone loss
- dna methylation
- gene expression
- dna binding
- bone mineral density
- human health
- immune response
- endothelial cells
- risk assessment
- binding protein
- metabolic syndrome
- type diabetes
- postmenopausal women
- adipose tissue
- oxidative stress
- cell cycle arrest
- insulin resistance
- signaling pathway
- inflammatory response
- cell death
- endoplasmic reticulum stress