Sex‐based differential regulation of bacterial‐induced bone resorption

Abstract

Background and Objective Periodontal disease pathogenesis is comprised of the complex inflammatory immune response to oral bacterial dysbiosis. Like other inflammatory diseases, there is sexual dimorphism evident in periodontal diseases. During periodontitis, inflammatory chemokines direct neutrophils to migrate to the site of infection to neutralize the pathogen. Interestingly, these same chemokines are also involved in regulating pathogen-induced osteoclast formation. Previous reports show differences in bone turnover and lymphocyte recruitment between sexes. We hypothesize that chemokine expression is differentially regulated by sex and thus result in differential osteoclast formation. Methods Male and female mice were utilized to isolate neutrophils based on expression of Ly6G-specific, as well as defined osteoclast progenitors (dOCPs). Cells were stimulated with LPS (100ng/ml) then analyzed for neutrophil infiltration and gene expression. dOCPs were primed: M-CSF (25ng/ml), RANKL (50ng/ml), then stimulated with LPS. Osteoclasts were enumerated via TRAP stain and mRNA isolated for gene expression analysis via qPCR. Results In response to LPS, male neutrophils in vitro respond with increased chemokine expression and significantly more osteoclast formed in response to LPS compared to females. Conclusions Findings support observations in humans regarding a sexual dimorphism in oral bacterial infections of alveolar bone loss. Males have a strong inflammatory response to bacterial infection, resulting in increased inflammatory microenvironment, reduced pathogenic bacteria clearance and increased osteoclast-driven bone loss in response to differential expression of key chemokines.

Inhibition of the histone demethylase KDM4B leads to activation of KDM1A, attenuates bacterial-induced pro-inflammatory cytokine release, and reduces osteoclastogenesis

“…Our data demonstrates that osteoclastogenesis proceeds normally with supplementation of either Aa-LPS or RANK-L but, when KDM4B is inhibited in pre-osteoclasts using ML324, neither of these additives induce significant osteoclast formation compared to vehicle control (Figure 4). This effect is seen in cells from both sexes, although there is a significantly higher number of osteoclasts formed in male cells compared to female cells, consistent with previous literature [45] ( Figure S3).…”

Cross‐sectional analysis of risk factors for subclinical periodontitis; active matrix metalloproteinase‐8 as a potential indicator in initial periodontitis in adolescents

“…). Also, sex‐specific differences may play a part in puberty and affect the host immune response to oral bacterial dysbiosis (Shiau and Reynolds, Valerio et al …”

“…Thus, girls seemed to have a lower risk compared with boys, which may be explained by some behavioral or environmental factors such as smoking (previously published in Heikkinen et al 4,5 ). Also, sex-specific differences may play a part in puberty and affect the host immune response to oral bacterial dysbiosis (Shiau and Reynolds, 37 Valerio et al 38 ).…”

The Sex and Gender Intersection in Chronic Periodontitis

“…In summary, given that the innate immune response might be more regulated in women ( 53 ) and more intense in men, women tend to be more effective at pathogen clearance compared to men. In addition, exposure of NK cells to estrogens increases INF-γ production ( 59 ), which has been shown to play a controversial role in periodontitis, with in vivo studies confirming an association with bone resorption and in vitro studies showing an inhibitory role in osteoclastogenesis ( 60 , 61 ). At the final level of inflammation resolution, there are indications that women may produce higher levels of resolvins due to increased synthesis of long-chain n-3 PUFA, leading to more effective periodontal inflammation resolution ( 27 ).…”