Female LSD1 Conditional Knockout Mice Have an Increased Bone Mass

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 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 results in a decrease in osteoclast differentiation and activity. Furthermore, Lsd1cKO female, but not male, mice have an increased bone mass. 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.