Inflammasome found to drive male-specific bone loss in gum disease

A study out of the University of North Carolina at Chapel Hill has unveiled new insights into the inflammatory processes behind periodontitis, a common and debilitating gum disease. Research conducted by UNC Adams School of Dentistry’s Julie Marchesan, DDS, Ph.D., and UNC School of Medicine’s Jenny Y. Ting, Ph.D., found that a part of the immune system called the inflammasome plays a key role in disease development, and that blocking this system prevents bone resorption only in males.

The study, published in the journal Proceedings of the National Academy of Sciences, suggests developing treatments specifically for male patients can have benefits and prompted an exploration of different biological mechanisms responsible for bone loss in females.

Periodontitis, inflammation-driven bone loss around the teeth, affects millions of people worldwide. While the disease is common across genders, it disproportionately impacts men, with males experiencing more severe symptoms.

“Our paradigm-shifting work not only pinpoints the inflammasome as a causal driver of male-biased periodontitis but also demonstrates a clear path for the development of sex-stratified therapeutics in periodontics,” Marchesan said. “Prior to this work, the inflammasome was believed to have the same role in the development of inflammatory conditions in both females and males. Our findings will foster the development of therapies that target the inflammasome and can specifically benefit male patients, while also paving the way for the discovery of biological mechanisms responsible for periodontitis in females.”

The study analyzed more than 6,200 human samples across three independent studies. Its findings showed that males exhibit significantly higher levels of interleukin-1 beta (IL-1β) in the gingival crevicular fluid during both healthy and periodontitis-affected states. This finding suggests that males may be more susceptible to inflammation-driven bone loss due to heightened IL-1β activity.

To further investigate this, the research team used mouse models and found male mice displayed greater IL-1β secretion than females. In addition, male mice with inflammasome gene deletions showed reduced bone loss. Applying a pharmacologic caspase-1/4 inhibitor to block inflammasome activity led to a significant reduction in inflammatory cell infiltration and a decrease in osteoclastogenesis signaling, which contributes to bone resorption. This intervention was effective in male mice but did not impact female mice, suggesting that the inflammasome’s role in periodontitis is gender-specific.

Researchers also tested male and female mice with their testes and ovaries removed, and found that male mice lost their response to caspase-1/4 inhibition. The female mice showed no change in their lack of response, further supporting the idea that the male reproductive system plays a crucial role in inflammasome-driven inflammation.

The study highlights the need for sex-specific research to fully understand the mechanisms behind inflammatory diseases. Given the prominent role of the inflammasome in driving male-biased periodontitis, further investigation into inflammasome-targeted treatments may offer a new avenue for improved patient care.