The effect of LSD1 and HDAC1-2 on osteoclast differentiation.

Abstract

Bone consists of several different cell types. Osteoblasts which form bone and osteoclasts which resorb bone. Bone remodeling occurs on a regular basis through coordination of osteoblast and osteoclast activity. Without it, our body’s skeleton would not be able to sustain form and function. Little is currently known about the epigenetic regulation of osteoclast differentiation. Lysine specific demethylase 1 (LSD1) regulates gene expression by removing lysines on histone 4 or 9. The Mansky lab demonstrated that mice with a conditional deletion of LSD1 in macrophages/osteoclast have smaller osteoclasts due to increase in interferon-β (IFN-β) genes. LSD1 has been previously shown to interact with histone deacetylase complexes (HDACs). We hypothesized that LSD1 and HDAC1 and HDAC2 work together to regulate IFN-β regulated genes in osteoclasts. To test this hypothesis gene expression of IFN-β regulated genes was measured in the presence of HDAC inhibitors in osteoclast precursors from wild type (WT) and LSD1 deficient osteoclasts (KO). Expression of IFN-β target genes Ifit1, Irf7, and Cxcl10 were measured by qRT-PCR. It was found that in the presence of HDAC inhibitors, IFN-β activates Ifit1, Irf7 and Cxcl10 but is reduced compared to IFN-β alone. The regulation by HDACs 1 and 2 does not appear to be dependent on LSD1 as there is no difference in the trends between the LSD1 WT and cKO cells. More research is needed to better understand the role of epigenetic proteins that regulate osteoclast gene expression. LSD1 and HDAC inhibitor 1 and 2 have notable effects on genes that are upregulated by IFN-β, but the full understanding of these effects is not evident. This research should open the door to more elaborate studies of these epigenetic proteins to aid in better comprehension of how they regulate the bone remodeling process.