Targeting histone deacetylases to suppress bone loss in similar chronic inflammatory diseases, periodontitis and rheumatoid arthritis.

Abstract

Rheumatoid arthritis (RA) and periodontitis are two common chronic inflammatory diseases characterized by soft tissue inflammation and associated bone loss. Despite the high prevalence of these conditions and our growing knowledge of the mechanisms involved in the disease processes, the control of bone destruction is still a challenging problem. For this reason it is important to identify anti-resorptive agents that may also inhibit inflammation which can be delivered orally upon diagnosis. Histone deacetylase inhibitors (HDACi) are one such potential therapeutic agent. The aim of this research was to use in vitro human peripheral blood mononuclear cells and human osteoclast assays in conjunction with animal models of periodontitis and inflammatory arthritis to determine the effects of novel HDACi (1179.4b which targets class I and II HDACs and NW-21 targets HDAC 1) on both inflammation and bone loss. The results of this thesis have identified that both RA and periodontitis are interrelated diseases, however, the specific HDACs involved in regulating the inflammatory and resorptive processes may be distinct. It is evident that, in arthritis, HDAC 1 is important in tissue inflammation, in periodontitis HDAC 1, 5, 8 and 9 are important and in osteoclasts HDAC 5 and 8 are up regulated. HDACi such as 1179.4b, NW-21 and MS-275 (class I specific HDACi) have been shown to have the potential to treat inflammatory bone loss. Further studies are necessary to elucidate the roles of each HDAC in RA and periodontitis and better target HDACi therapy.