The epigenetic role of Lysine Specific Demethylase 1 in Osteoclast Differentiation

Abstract

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 this study, little was known about the effect of LSD1 on skeletal development and osteoclast differentiation. Here, we show conditional deletion of LSD1 in both myeloid and monocyte lineages results in a decrease in osteoclast differentiation and activity. Furthermore, LSD1LysM-cKO females, but not males, have increased bone mass. Contrarily, LSD1Cfms-cKO males, but not females, have increased bone mass. We further 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. Lastly, we demonstrate that LSD1LysM-cKO male and female mice are resistant to periodontitis induced bone loss, suggesting that even in inflammatory conditions, LSD1 is important in driving osteoclast differentiation.