HDAC5-Mediated Acetylation of p100 Suppresses Its Processing
Introduction: Periodontitis is a condition characterized by chronic inflammation affecting the gums, periodontal ligaments, cementum, and alveolar bone. Activation of nuclear factor-κB (NF-κB) is a key mediator in both inflammation and osteoclast differentiation. However, the role of histone deacetylase 5 (HDAC5) in the development of periodontitis and its regulation of NF-κB remains poorly understood.
Methods: We utilized primary mouse bone marrow-derived osteoclast cultures in vitro and a mouse model of chronic periodontitis (CPD), treated with the selective HDAC4/5 inhibitor LMK-235. A variety of techniques, including real-time polymerase chain reaction, micro computed tomography, flow cytometry, western blot, and immunoprecipitation, were employed to examine proinflammatory cytokines, NF-κB activation, HDAC5 activity, and the interaction between HDAC5 and NF-κB p100.
Results: The selective inhibition of HDAC4 and HDAC5 by LMK-235 decreased the expression of osteoclast marker genes (Cstk, Acp5, and Calcr) and reduced tartrate-resistant acid phosphatase activity in primary osteoclast cultures. In the CPD mouse model, LMK-235 attenuated the increase in the cementoenamel junction-alveolar bone crest distance, reduced inflammatory cell infiltration in gingival tissues, and lowered the expression levels of proinflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor alpha, IL-6, and IL-23a, indicating its ameliorative effect on CPD. Immunoprecipitation further confirmed the interaction between p100 and HDAC5, as well as the acetylation of p100 and subsequent NF-κB activation.
Conclusions: Our findings suggest that HDAC5 binds to and deacetylates p100, which leads to its activation, promoting the production of proinflammatory cytokines, gingival infiltration, and osteoclast differentiation, ultimately driving alveolar bone resorption. Inhibiting HDAC5 presents a promising therapeutic strategy for the treatment of periodontitis.