Diseases such as osteoporosis and periodontal disease affect millions of individuals annually in the United States and cost billions in treatment. Osteoclasts are large, multinucleated cells that secrete acid and proteases to resorb bone. Understanding the molecular mechanisms that regulate osteoclast differentiation and activity will provide insight as to how the hyper-active osteoclasts causing pathological bone loss, contributes to osteoporosis and periodontal disease. Reversible modifications to DNA such as histone acetylation, methylation, phosphorylation and ubiquitylation alter the access of transcriptional machinery to DNA and regulate gene expression. Lysine-specific demethylase 1 (LSD1), also known as KDM1A, is the first identified histone demethylase capable of specially demethylating mono- and di-methylated lysine 4 of histone 3 (H3K4me1/2) or lysine 9 of histone 3 (H3K9me1/2). LSD1 confers transcriptional repression by demethylating H3K4 or activating transcription by demethylating H3K9. The mechanism by which LSD1 regulates osteoclast gene expression and differentiation is currently unknown. Preliminary data presented in this proposal demonstrate inhibition of LSD1 activity or expression leads to an increase in mono-methylation of H3K4me1 and an increase in osteoclast differentiation. These preliminary data suggest LSD1 is a repressor of osteoclast gene expression. This proposal aims to characterize the role of LSD1 in regulating osteoclast differentiation in both an animal model and as well as in an in vitro cell culture model (Aim 1) and identifying the osteoclast genes that are regulated by LSD1 (Aim 2). These research goals will be enhanced by the training goals of the application. These training goals include learning techniques such as micro-CT, RNA-SEQ and ChIP-SEQ as well as participation in journal clubs and local and national scientific meetings. Training takes place at the University of Minnesota which offers an outstanding environment for both research and clinical dental training.
Osteoclasts are cells that break down bone during normal growth and repair, playing a significant role in bone destructive diseases like osteoporosis, periodontal disease, cancer, and arthritis. This project aims to determine if lysine-specific demethylase 1 (LSD1), a protein that regulates osteoclast formation by removing methyl groups from histones, inhibits osteoclast formation and activity. Understanding the molecular mechanisms governing the activity of LSD1 may lead to development of pharmaceutical treatments for diseases associated with increased bone resorption.
