Analyzing Loss of HDAC4 Expression: Effect on Osteoclastogenesis

Abstract

Histone deacetylases (HDACs) are intracellular enzymes that directly affect chromatin structure and transcription factor activity. HDACs have become an important focus in research due to their role in many fundamental processes including differentiation, growth arrest and apoptosis. It has been demonstrated that skeletal formation is regulated by HDACs in their ability to repress transcription factors required in osteoblastogenesis and osteoclastogenesis. These findings have immense clinical implications for HDACs as therapeutic agents. In this study, I seek to understand more about the role of a specific HDAC during osteoclast differentiation. It has recently been shown that HDAC7, a Class IIa HDAC, suppresses osteoclastogenesis when over-expressed and that loss of expression increases osteoclastogenesis. These effects are opposite of those reported with loss of Class I HDAC expression and broad spectrum HDAC inhibitors. My experiments are the first to examine another Class IIa HDAC, HDAC 4 and its role during osteoclastogenesis. My results demonstrate loss of HDAC4 expression leads to enhanced osteoclast differentiation and activity. Furthermore in the absence of HDAC7, loss of HDAC4 expression leads to a further enhancement of osteoclast differentiation and activity. Overall my results demonstrate a role for HDAC4 in regulating osteoclast differentiation and activity unique from the role previously demonstrated for HDAC7.