Histone deacetylase inhibitors and periodontal bone loss

Abstract

Cantley MD, Bartold PM, Marino V, Fairlie DP, Le GT, Lucke AJ, Haynes DR. Histone deacetylase inhibitors and periodontal bone loss. J Periodont Res 2011; 46: 697–703. © 2011 John Wiley & Sons A/S Background and Objective: Bone loss caused by enhanced osteoclast activity is a significant feature of periodontitis. Histone deacetylase inhibitors (HDACi) can suppress osteoclast‐mediated bone loss in vitro and in vivo. This study investigated whether HDACi can suppress bone loss in experimental periodontitis. Material and methods: Experimental periodontitis was induced in mice by oral inoculation with Porphyromonas gingivalis bacteria. Mice were treated orally with olive oil alone, with olive oil and a novel compound – 1179.4b – which targets both Class I and Class II histone deacetylases (HDACs) or with olive oil and MS‐275, which targets Class I HDACs. Micro‐computed tomography scans of live mice, stereo imaging and histological analyses were used to detect changes in bone. Results: In the absence of treatment there was a 13.2% increase in bone volume in controls compared with a 7.4% decrease in P. gingivalis‐inoculated mice. 1179.4b significantly reduced bone loss, with a 3.4% increase in bone volume (p < 0.01). MS‐275 did not have a significant effect on P. gingivalis‐induced bone loss. Histological analysis revealed that 1179.4b reduced bone loss despite having no effect on inflammation. Conclusion: HDACi were found to effectively suppress bone loss in the mouse model of periodontitis. 1179.4b – the inhibitor of Class I and Class II HDACs – was more effective at suppressing bone loss than MS‐275, which targets Class I HDACs only. These compounds may therefore have the potential to be used for the management of periodontitis.

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

“…It is important to note that the dosage used in this model was 100x lower compared to other broad acting HDACi such as vorinostat used in the treatment of malignancies. It is interesting that in the same periodontitis animal model, the HDAC-1 selective inhibitor MS-275 (Table 3) administered orally at 10 mg/kg/day reduced levels of inflammation but had no effect on bone loss [90]. We have also…”

“…Using a mouse model of P. gingivalis-induced periodontitis, oral administration of this broad acting HDACi 1179.4b (1 mg/kg/day for 36 days) suppressed alveolar bone loss with an accompanying reduction in the number of TRAP positive cells in the gingiva and alveolar bone [90]. Interestingly, whilst inhibiting bone resorption, 1179.4b did not suppress gingival inflammation.…”

“…The potential of HDACi to treat periodontitis has been recently demonstrated using a novel HDACi, 1179.4b, shown to suppress alveolar bone loss in periodontitis [90]. Using a mouse model of P. gingivalis-induced periodontitis, oral administration of this broad acting HDACi 1179.4b (1 mg/kg/day for 36 days) suppressed alveolar bone loss with an accompanying reduction in the number of TRAP positive cells in the gingiva and alveolar bone [90].…”

Epigenetics - A Window Towards Personalized Periodontal Therapy

“…Treatment by HDAC inhibitors efficiently suppressed periodontal bone loss in a mouse model of periodontitis [13].Treatment with novel HDAC inhibitors, such as 1179.4b (class I, II HDACi )and MS-275 (class I HDACi), on P.gingivalis-inoculated mice resulted in significantly reduced P.gingivalis induced bone loss with 1179.4b, whereas MS-275 had no significant effect, indicating that maintenance of acetylation is crucial to preventing bone loss and no influence was found on the level of inflammation. HDACi prevent bone loss and demonstrates that the novel HDACi, 1179.4b reduces alveolar bone loss in an in vivo model of periodontitis [13].…”

“…Class I includes HDACs 1, 2, 3 and 8, which are found in the nucleus. Class II includes HDACs 4, 5, 7 and 9 that belong to class II a HDACs and HDACs 6 and 10 belonging to class II b HDACs, which are able to shuttle between the nucleus and the cytoplasm [13].…”