Inhibition of the Histone Demethylase KDM4B Leads to Activation of KDM1A, Attenuates Bacterial-Induced Pro-Inflammatory Cytokine Release and Reduces Osteoclastogenesis

Description:

Technology:  Researchers at MUSC have discovered a series of novel small molecules that contain potent immunosuppressive activity and can be used as the new treatment for periodontal disease (PD). PD is caused by bacteria infection in dental plaque, which leads to the inflammation response in the area of gums, periodontal ligament or alveolar bone. While most therapy for PD targets bacteria, the host immune response is responsible for driving tissue damage and bone loss in severe PD. MUSC researchers established that the histone demethylase KDM4B is a potential drug target for the treatment of PD (Figure 1).

Experimental results both in vitro and in vivo have shown that the abundance of KDM4B is correlated with inflammation, and inhibition significantly reduces the As-LPS-induced immune response in primary macrophages, with a significant reduction of IL-6 and TNF-α expression and secretion (data not shown). Moreover, KDM4B inhibition with a previously identified inhibitor ML324 prevents osteoclast formation induced by As-LPS or RANK-L in murine bone marrow (Figure 2). The data indicates that the immunosuppression promoted by KDM4B inhibition reduces osteoclastogenesis, a main factor of PD.