Role of histone deacetylases in bone development and skeletal disorders

Abstract

Bone cells must constantly respond to hormonal and mechanical cues to change gene expression programs. Of the myriad of epigenomic mechanisms used by cells to dynamically alter cell type-specific gene expression, histone acetylation and deacetylation has received intense focus over the past two decades. Histone deacetylases (HDACs) represent a large family of proteins with a conserved deacetylase domain first described to deacetylate lysine residues on histone tails. It is now appreciated that multiple classes of HDACs exist, some of which are clearly misnamed in that acetylated lysine residues on histone tails is not the major function of their deacetylase domain. Here, we will review the roles of proteins bearing deacetylase domains in bone cells, focusing on current genetic evidence for each individual HDAC gene. While class I HDACs are nuclear proteins whose primary role is to deacetylate histones, class IIa and class III HDACs serve other important cellular functions. Detailed knowledge of the roles of individual HDACs in bone development and remodeling will set the stage for future efforts to specifically target individual HDAC family members in the treatment of skeletal diseases such as osteoporosis.

Keywords: Bone development; Histone deacetylase; Salt inducible kinase; Sirtuin.

Figure 1.

Overview of domain structure, subcellular localization, and catalytic activity for the HDAC subclasses reviewed here.

Figure 2.

Model demonstrating parallels between cAMP signaling via a SIK/class IIa HDAC axis in growth plate chondrocytes (left) and osteocytes (right).