Interleukin-33 and RANK-L Interplay in the Alveolar Bone Loss Associated to Periodontitis

Abstract

IntroductionChronic Periodontitis (CP) is an inflammatory disease of bacterial origin that results in alveolar bone destruction. Porphyromonas gingivalis (Pg), one of the main periopathogens, initiates an inflammatory cascade by host immune cells thereby increasing recruitment and activity of osteoclasts, the bone resorbing cells, through enhanced production of the crucial osteoclastogenic factor, RANK-L. Antibodies directed against some cytokines (IL-1β, IL-6 and TNF-α) failed to exhibit convincing therapeutic effect in CP. It has been suggested that IL-33, could be of interest in CP.Objectivethe present study aims to analyze whether and how IL-33 and RANK-L and/or their interplay are involved in the bone destruction associated to CP.Material and MethodsmRNAs and protein expressions of IL-33 and RANK-L were analyzed in healthy and CP human gingival samples by immunohistochemistry (IHC) and RT-qPCR. Murine experimental periodontitis (EP) was induced using Pg infected ligature and Pg free ligature around the first maxillary molar. Alveolar bone loss was recorded by μCT. Mouse gingival explants were stimulated for 24 hours with IL-33 and RANK-L mRNA expression investigated by RT-qPCR. Human oral epithelial cells were infected by Pg for 6, 12; 24 hours and IL-33 and RANK-L mRNA expressions were analyzed by RT-qPCR.ResultsIL-33 is overexpressed in gingival epithelial cells in human affected by CP as in the murine EP. In human as in murine gingival cells, RANK-L was independently induced by Pg and IL-33. We also showed that the Pg-dependent RANK-L expression in gingival epithelial cells occured earlier than that of IL-33.ConclusionOur results evidence that IL-33 overexpression in gingival epithelial cells is associated with CP and may trigger RANK-L expression in addition to a direct effect of Pg. Finally, IL-33 may act as an extracellular alarmin (danger signal) showing proinflammatory properties in CP perpetuating bone resorption induced by Pg infection.

Elevated levels of 8‐OHdG and PARK7/DJ‐1 in peri‐implantitis mucosa

“…Finally, as there are no previous studies available on 8-OHdG, NFE2L2/NRF2, and PARK7/ DJ-1 levels in oral tissues, the study size was defined according to studies, where immunohistochemical methods were used to determine the tissue levels of immune response proteins in gingival biopsies collected from individuals with periodontitis. 24,31 The measurement of 8-OHdG levels is considered a reliable technique for the detection of elevated oxidative stress, and increased 8-OHdG levels have been demonstrated in mouse and human In the present study, the number of NFE2L2/NRF2 stained epithelial cells in peri-implantitis, periodontitis, and control samples was similar. Also, the majority of NFE2L2/NRF2 positive cells was localized at the epithelium, while only a limited number of NFE2L2/NRF2 positive cells was seen in the connective tissue.…”

“…In the present study, control tissue samples were obtained during crown lengthening procedures of periodontally healthy individuals without signs of clinical inflammation (no bleeding on probing) in sampling sites, however, subclinical inflammation was observed in a few samples. Finally, as there are no previous studies available on 8-OHdG, NFE2L2/NRF2, and PARK7/ DJ-1 levels in oral tissues, the study size was defined according to studies, where immunohistochemical methods were used to determine the tissue levels of immune response proteins in gingival biopsies collected from individuals with periodontitis 24,31. Therefore, in the absence of previous radiographic recordings, we followed the guidelines of the consensus report,22 and a threshold of 3 mm was applied to define peri-implantitis related bone loss.…”

ST2 regulates bone loss in a site‐dependent and estrogen‐dependent manner

“…In the maxillae, IL-33 and ST2 are expressed in alveolar bone and periodontal ligament cells, 15,16 and they seem to exert bimodal effects. The alveolar bone loss seen in the pathological periodontal condition includes increases in IL-33 in human gingival samples [16][17][18] and in a murine periodontitis model, 16,18,19 as IL-33 is associated with increased RANKL expression. 16,17,19 Nevertheless, IL-33 also participates in the maintenance of alveolar bone architecture under physiological conditions and mechanical stimulation, reducing osteoclast formation and activity by inducing apoptosis.…”

Denervation effectively aggravates rat experimental periodontitis

“…39 IL-1β contributes to connective tissue destruction in part by upregulating MMP-3. 40 These mediators may affect the activities of leukocytes, osteoblasts and osteoclasts systemically and locally, and mediate MMPs, which are tissue-destructive proteolytic enzymes. IL-1 and TNFα promote the recruitment and activity of the bone resorbing cells, the osteoclasts, by enhancing production of a crucial osteoclastogenic factor, the RANKL, and favor bone destruction.…”

“…TNF‐α upregulates the production of collagenases, prostaglandin E 2 , cell adhesion molecules and bone resorption‐related factors . IL‐1β contributes to connective tissue destruction in part by upregulating MMP‐3 . These mediators may affect the activities of leukocytes, osteoblasts and osteoclasts systemically and locally, and mediate MMPs, which are tissue‐destructive proteolytic enzymes.…”