Novel approaches to reduce osteoclastic bone loss are needed for a number of exceedingly common clinical conditions including osteoporosis, metastatic bone disease, periodontitis, and arthritis; conversely, strategies to increase osteoclast function are necessary to correct the lack of bone resorption in conditions including osteopetrosis. To improve our ability to clinically manipulate osteoclast activity will require a deeper understanding of the molecular mechanisms that govern their physiology. We have identified histone deacetylase 7 (HDAC7) as a negative regulator of osteoclast differentiation that has potential implications for the development of new therapies. While inhibition of other HDACs impairs osteoclastogenesis, preliminary studies reveal a unique function for HDAC7 in osteoclasts. Suppression of HDAC7 enhances their formation, while their formation is impaired by overexpression of HDAC7. Using the LysM-Cre mouse, which targets osteoclasts, we have preliminary data demonstrating that at 3 months of age HDAC7-null mice are osteopenic due to enhanced osteoclastogenesis. Further data indicate that these effects are mediated through RANKL-regulated interactions between HDAC7 and the MITF transcription factor. These results suggest that reduced HDAC7 activity in osteoclastic cells may contribute to pathological bone loss, whereas stimulation of HDAC7 might represent a novel strategy to clinically reduce bone loss. However, the current incomplete understanding of HDAC7's function in osteoclasts limits the rational development of such diagnostic or therapeutic approaches. Our central hypothesis is that HDAC7 is a negative regulator of osteoclast differentiation and functions by repressing the activation of MITF and PU.1 (and potentially other transcription factors). RANKL signaling through the p38 MAP kinase pathway disrupts these repressive interactions, enabling efficient osteoclast gene expression and subsequent differentiation. We will test this hypothesis with three specific aims: 1) Characterize the in vivo phenotype and cellular effects of conditional knockout of HDAC7 in osteoclast progenitors; 2) Characterize the molecular mechanisms by which HDAC7 regulates osteoclast differentiation; and 3) Determine the mechanism and biological significance of RANKL regulation of MITF/PU.1-HDAC7 interaction. Completion of these aims will significantly increase our knowledge concerning a unique regulatory pathway in osteoclasts, advance the search for improved therapeutic strategies for aberrant bone loss and ultimately lead to be better clinical outcomes.
NIH ExPorter
NIH ExPorter