Histone Lys demethylase KDM3C demonstrates anti‐inflammatory effects by suppressing NF‐κB signaling and osteoclastogenesis

Abstract

Histone Lys‐specific demethylases (KDMs) play a key role in many biological processes through epigenetic mechanisms. However, the role of KDMs in inflammatory responses to oral bacterial infection is poorly understood. Here, we show a novel regulatory role of KDM3C in inflammatory responses to oral bacterial infection. KDM3C expression is transiently suppressed in human and mouse macrophages exposed to LPS from Porphyromonas gingivalis (Pg LPS). Loss of KDM3C in both human and mouse macrophages led to notable induction of proinflammatory cytokines in response to Pg LPS stimulation. Also, KDM3C depletion led to strong induction of p65 phosphorylation and accelerated nuclear translocation in cells exposed to Pg LPS. Kdm3C knockout (KO) in mice led to increased alveolar bone destruction upon induction of experimental periodontitis or pulp exposure compared with those of the wild‐type (WT) littermates. The Kdm3C KO mice also revealed an increased number of osteoclasts juxtaposed to the bony lesions. We also confirmed enhanced osteoclastogenesis by bone marrow–derived macrophages isolated from the Kdm3C KO compared with the WT controls. These findings suggest an anti‐inflammatory function of KDM3C in regulating the inflammatory responses against oral bacterial infection through suppression of NF‐κB signaling and osteoclastogenesis.—Lee, J. Y., Mehrazarin, S., Alshaikh, A., Kim, S., Chen, W., Lux, R., Gwack, Y., Kim, R. H., Kang, M. K. Histone Lys demethylase KDM3C demonstrates anti‐inflammatory effects by suppressing NF‐κB signaling and osteoclastogenesis. FASEB J. 33, 10515–10527 (2019). http://www.fasebj.org

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition

“…Moreover, the pharmacological inhibition of the histone Lys demethylase JMJD3 protected mice against early septic death and reduced pro-inflammatory cytokine production via up-regulation of miR-146a [145]. Similarly, histone demethylase KDM3C demonstrated an anti-inflammatory effect by suppressing NF-κB signaling against oral bacterial infection in mice [146].…”

Histone Methylation: Achilles Heel and Powerful Mediator of Periodontal Homeostasis

“…Knockdown of the Jmjd3 gene reduced demethylation of H3K27me3 at the transcription start site of Nfatc1 and suppressed RANKL-induced osteoclast differentiation, indicating that JMJD3 functions to modulate RANKL-induced osteoclastogenesis (Yasui et al 2011). In addition, knockdown of KDM3/JMJD1C suppressed NF-ΚB signaling and osteoclastogenesis (Lee et al 2019).…”

Genetic and Epigenetic Characterization of Pulpal and Periapical Inflammation

“…Recently, regulatory effects of KDM3C were demonstrated on oral inflammatory lesions, including AP induced by pulp exposure and experimentally induced periodontitis by ligature placement (Lee et al, 2019). KDM3C is a member of JmjC-domain containing KDMs with demethylase activity specific for H3K9 moieties (Peeken et al, 2018).…”