Monocyte Subsets With High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Abstract

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).

Aberrant activation of TGF-β1 induces high bone turnover via Rho GTPases-mediated cytoskeletal remodeling in Camurati-Engelmann disease

“…Excessive osteoclast activity leads to bone loss and osteoporosis ( 16 ). Osteoclasts were used to assess the regulatory function of TGF-β1 because of the lower bone mineral density in CED patients and the high expression of osteoclast marker ACP5 in their peripheral blood.…”

“…Osteoclasts maintain the balance of bone metabolism in the body by cooperating with osteoblasts. Excessive activity of osteoclasts leads to bone loss; thus, understanding the activities of osteoclasts is necessary for developing therapeutic strategies against osteoclast-related disorders ( 16 ). Although the relationship between Rho GTPases and bone metabolism is well-documented, the role of Rho GTPases in regulating TGF-β1-induced osteoclast production remains ambiguous.…”

The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

“…Flow cytometry analysis revealed an 81.06% increase in the number of osteoclast progenitors, defined as Lin − CD11b − Ly6C hi CD115 + [ 48 , 49 , 50 , 51 ], in the EPO injected mice. However, this was reduced by 42.8% in the EPO + Cibinetide-injected mice compared to the EPO-injected mice, without any change in the numbers of osteoblast precursors ( Figure 7 a).…”

Ezh2 mediates epigenetic regulation of osteoclastogenesis and bone remodeling in mice

“…It has recently been reported that both homo and heterozygous of IRF8 gene mutations promote osteoclastogenesis and increased osteoclast activity, which is accompanied by increased NFATc1 expression (Izawa et al , 2019). IRF8 plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor to differentiate into a monocyte precursor cell (Das et al , 2020). The LysM-Cre mouse model used in our current study has a nuclear-localized Cre recombinase inserted into the first coding ATG of the lysozyme 2 gene (Lyz2); both abolishing endogenous Lyz2 gene function and placing NLS-Cre expression under the control of the endogenous Lyz2 promoter/enhancer elements (The Jackson Laboratory).…”