Histone deacetylases in skeletal development and bone mass maintenance

Abstract

The skeleton is a multifunctional and regenerative organ. Dynamic activities within the bone microenvironment necessitate and instigate rapid and temporal changes in gene expression within the cells (osteoclasts, osteoblasts, and osteocytes) responsible for skeletal maintenance. Regulation of gene expression is controlled, in part, by histone deacetylases (Hdacs), which are intracellular enzymes that directly affect chromatin structure and transcription factor activity. Key roles for several Hdacs in bone development and biology have been elucidated though in vitro and in vivo models. Recent findings suggest that clinical usage of small molecule Hdac inhibitors for conditions like epilepsy, bipolar disorder, cancer, and a multitude of other ailments may have unintended effects on bone cell populations. Here we review the progress that has been made in the last decade in understanding how Hdacs contribute to bone development and maintenance.

Differential Anti-inflammatory Activity of HDAC Inhibitors in Human Macrophages and Rat Arthritis

“…Thus, exacerbation of disease symptoms with vorinostat and BML281 at 5 mg×kg 21 may relate to both increased macrophage infiltration and release of TNFa and IL1b. These cytokines may subsequently mediate macrophage differentiation and fusion to giant multinucleated osteoclasts that ultimately contribute to the heightened disease pathologies observed (Schroeder and Westendorf, 2005;McGee-Lawrence and Westendorf, 2011). These require further clarification in future in vitro studies.…”

HDAC Inhibition in Lupus Models

“…To date, only 18 genes have been identified as HDAC and these are subdivided into four classes based on structural and functional similarities (18). Class I HDACs (HDAC1, -2, -3, -6, and -8) are expressed in a wide range of tissues and found exclusively in the nucleus (19,20,21).…”

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

“…Bone production is controlled by gene expression programs in osteoblasts that mediate deposition of collagens and noncollagenous proteins into an extracellular matrix (ECM) 3 that ossifies through nucleation of minerals (e.g. hydroxyapatite) (5). The adult skeleton is constantly remodeled to accommodate physiological demands and restore bone fractures.…”