Epigenetic Regulation of Cells Involved in Periodontal Bone Destruction through Targeted Histone Deacetylase Inhibition

Abstract

Periodontitis (PD) is one of the most common bone loss pathologies in adults and currently affects more than 60% of the population in its destructive form. Ineffective or surgically invasive treatment options can result in patient noncompliance, gingival recession, alveolar bone destruction and eventual loss of teeth. Aside from the psychosocial effects of poor dental health, PD has been associated with a variety of systemic conditions, such as rheumatoid arthritis and cardiovascular disease, exacerbating their onset and severity. Histone deacetylase (HDAC) enzymes are molecules that control cellular activity through modifications to gene expression and protein function at an epigenetic level. Alterations to HDAC expression or function can cause diminished physiological cell regulation, thought to be an essential factor in the pathogenesis of disease. The use of selective HDAC inhibitors (HDACi) targeting candidate HDACs may be an effective, non-invasive therapeutic tool to treat both inflammation and bone loss in PD. The aim of this research was to investigate the effects of novel HDACi designed to target individual HDAC isoforms as a PD treatment. In vitro investigations identified therapeutic potential for targeting HDAC 1 and HDAC 2 during the inflammatory response and catabolic actions of human monocytes and osteoclasts. Whereas HDAC 5 inhibition holds regenerative potential, as osteoblastogenesis and matrix mineralisation was induced by its suppression. With the additional identification and characterisation of candidate HDAC isoforms in an in vivo mouse model of PD, the results of this thesis will provide a strong foundation for future investigations and clinical translation of HDACi.