Targeting NLRP3 Inflammasome Reduces Age-Related Experimental Alveolar Bone Loss

Abstract

The cause of chronic inflammatory periodontitis, which leads to the destruction of periodontal ligament and alveolar bone, is multifactorial. An increasing number of studies have shown the clinical significance of NLRP3-mediated low-grade inflammation in degenerative disorders, but its causal linkage to age-related periodontitis has not yet been elucidated. In this study, we investigated the involvement of the NLRP3 inflammasome and the therapeutic potential of NLRP3 inhibition in age-related alveolar bone loss by using in vivo and in vitro models. The poor quality of alveolar bones in aged mice was correlated with caspase-1 activation by macrophages and elevated levels of IL-1β, which are mainly regulated by the NLRP3 inflammasome, in periodontal ligament and serum, respectively. Aged mice lacking Nlrp3 showed better bone mass than age-matched wild-type mice via a way that affects bone resorption rather than bone formation. In line with this finding, treatment with MCC950, a potent inhibitor of the NLRP3 inflammasome, significantly suppressed alveolar bone loss with reduced caspase-1 activation in aged mice but not in young mice. In addition, our in vitro studies showed that the addition of IL-1β encourages RANKL-induced osteoclastogenesis from bone marrow–derived macrophages and that treatment with MCC950 significantly suppresses osteoclastic differentiation directly, irrelevant to the inhibition of IL-1β production. Our results suggest that the NLRP3 inflammasome is a critical mediator in age-related alveolar bone loss and that targeting the NLRP3 inflammasome could be a novel option for controlling periodontal degenerative changes with age.

NLRP3 regulates alveolar bone loss in ligature‐induced periodontitis by promoting osteoclastic differentiation

“…These results are in contrast with those of a study that used a Porphyromonas gingivalis oral colonization model of experimental periodontitis, which showed a significant attenuation of bone resorption in NLRP3‐deficient mice 12 . Thereafter, another well‐done and extensive study used ageing‐related periodontitis as an in vivo model, suggested that NLRP3 plays an important role in osteoclastogenesis during ageing 29 . However, ageing is a very complex process.…”

“…The main findings of the present study are as follows ( Thereafter, another well-done and extensive study used ageing-related periodontitis as an in vivo model, suggested that NLRP3 plays an important role in osteoclastogenesis during ageing. 29 However, ageing is a very complex process. Besides NLRP3 mediated inflammation, osteoclast differentiation in ageing has been affected by many other factors.…”

Inflammasomes in Alveolar Bone Loss

“…Among these inflammasomes, NLRP3 has been widely studied in periodontitis. NLRP3 infl ammasome activation in inflammatory periodontal tissue can be triggered by local factors such as the crystalline structure of dental calculus, aggravated by systemic factors such as hyperglycemic status of type 2 diabetes mellitus and age-related oxidative stress, or alleviated by 1,25-dihydroxyvitamin D3 (157)(158)(159)(160)(161)(162). NLRP3 inflammasome activation is also required for the synergistic effects of periodontal pathogens and cholesterol crystals on promoting IL-1b secretion in PBMCs, suggesting its role in the interplay between periodontal disease and cardiovascular disease (233).…”

The Role of NLRP3 Inflammasome Activities in Bone Diseases and Vascular Calcification

“…Similarly, MCC950 inhibited osteoclast differentiation and reduced caspase-1 activation. This phenomenon was not observed in young mice [71]. Cell death can be classified as apoptosis, necroptosis, pyroptosis, autophagic cell death, and other forms of cell death.…”