Regulation of Osteoclast Differentiation and Skeletal Maintenance by Histone Deacetylases

Abstract

Bone is a dynamic tissue that must respond to developmental, repair, and remodeling cues in a rapid manner with changes in gene expression. Carefully-coordinated cycles of bone resorption and formation are essential for healthy skeletal growth and maintenance. Osteoclasts are large, multinucleated cells that are responsible for breaking down bone by secreting acids to dissolve the bone mineral and proteolytic enzymes that degrade the bone extracellular matrix. Increased osteoclast activity has a severe impact on skeletal health, and therefore, osteoclasts represent an important therapeutic target in skeletal diseases, such as osteoporosis. Progression from multipotent progenitors into specialized, terminally-differentiated cells involves carefully-regulated patterns of gene expression to control lineage specification and emergence of the cellular phenotype. This process requires coordinated action of transcription factors with co-activators and co-repressors to bring about proper activation and inhibition of gene expression. Histone deacetylases (HDACs) are an important group of transcriptional co-repressors best known for reducing gene expression via removal of acetyl modifications from histones at HDAC target genes. This review will cover the progress that has been made recently to understand the role of HDACs and their targets in regulating osteoclast differentiation and activity and, thus, serve as potential therapeutic target.