LSD1 Conditional Knockout Mice Have an Increased Bone Mass Due to Increased IFN-B Gene Expression

Osteoclasts are large multinucleated cells that degrade bone mineral and extracellular matrix. Investigating the mechanisms by which osteoclast differentiation is epigenetically regulated is a key to understanding the pathogenesis of skeletal related diseases such as periodontitis and osteoporosis. Lysine specific demethylase 1 (LSD1/KDM1A) is a member of the histone demethylase family that regulates gene expression via the removal of mono- and dimethyl groups from H3K4 and H3K9. Prior to our study, little was known about the effect of LSD1 on skeletal development and osteoclast differentiation. Here we show conditional deletion of LSD1 in the myeloid lineage or macrophage/osteoclast precursors results in a decrease in osteoclast differentiation and activity. Our bulk RNA-SEQ data suggests that osteoclast differentiation is inhibited in LSD1cKO mice due to an increase in expression of IFN-b target genes. Lastly, we demonstrate that LSD1 can form a complex with CoREST, HDAC1 and HDAC2 suggesting a mechanism by which the combination of methylation and acetylation of histone residues regulates osteoclast gene expression. Bone marrow macrophages were isolated from LSD1 WT mice (LSD1 floxed mice) and LSD1cKO mice (LSD1;LysM-Cre) female mice. Bone marrow macrophages were cultured in M-CSF and RANKL for 2 days. We performed gene expression analysis of RNA-SEQ of three mice of each genotype at one time point.