New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis.

Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases leading to increased bone resorption. Preventing this inflammatory bone resorption is a major health challenge. Both diseases share immunopathogenic similarities and a common inflammatory environment. The autoimmune response or periodontal infection stimulates certain immune actors, leading in both cases to chronic inflammation that perpetuates bone resorption. Moreover, RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis. This dysbiosis is believed to be involved in the initiation of RA via three mechanisms. (i) The dissemination of periodontal pathogens triggers systemic inflammation. (ii) Periodontal pathogens can induce the generation of citrullinated neoepitopes, leading to the generation of anti-citrullinated peptide autoantibodies. (iii) Intracellular danger-associated molecular patterns accelerate local and systemic inflammation. Therefore, periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints. Interestingly, in inflammatory conditions, the existence of osteoclasts distinct from "classical osteoclasts" has recently been reported. They have proinflammatory origins and functions. Several populations of osteoclast precursors have been described in RA, such as classical monocytes, a dendritic cell subtype, and arthritis-associated osteoclastogenic macrophages. The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions, especially in RA and periodontitis. Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases. Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.

Effectiveness of treatment by coronoidectomy and active rehabilitation in Langenbeck or Jacob diseases. A retrospective study of 20 cases.

BACKGROUND: The objective of this study was to evaluate the mouth opening (MO) in patients with Langenbeck or Jacob diseases after a multimodal treatment combining the coronoidectomy and a self or assisted postoperative rehabilitation. METHODS: This observational retrospective study included patients who had clinically impacted MO limitation. All patients underwent unilateral or bilateral coronoidectomy and then physical therapy for at least 3 months. MO measurements were compared between the preoperative time (M0), the immediate postoperative time (M1) and the last follow-up (M2). Other data regarding the surgical procedure and the postoperative rehabilitation were collected. RESULTS: Twenty patients were included. The MO was significantly improved from 19.15 ± 7.02 mm at M0 to 38.00 ± 7.62 mm at M1 (p = 0.0002). After a mean follow-up of 21.5 ± 40.5 months, the mean MO was 32.85 ± 5.69 mm (M2). All patients underwent coronoidectomy through an intraoral approach except for one patient who was given a combined extra-oral approach for a recurrent disease. Rehabilitation protocol included assisted physiotherapy and self-rehabilitation in 7 patients as well as just self-rehabilitation in 13 patients. No patient showed worsening or stagnation of MO. CONCLUSIONS: The multimodal treatment combining the surgical removal of the coronoid process and an active rehabilitation performed by the patient himself or assisted by a physiotherapist seems effective in Langenbeck or Jacob diseases.

GUIDED PERI-IMPLANT AUTOGENOUS SOFT TISSUE GRAFTING: CASE REPORT.

This case report showed the proof-of-concept of a guided free gingival graft around a dental implant. A 65-year-old male presented to replace his 30 and 31. Once the osseointegration of the 2 implants placed by guided surgery has been achieved, a free gingival graft was indicated. The surgical planning of this graft was performed using the Cone Beam Computed Tomography and archs digital scanning already used for implant placement. The greater palatine foramen and gutter were radiologically located to protect their arterial content. Two surgical guides were designed, one for the palatal donor site and one for the recipient site. The first one will serve both as an incision guide and as a post-operative protective plate. The procedure was free of adverse events. At the 1-year recall, the average gain in keratinized tissue width amounted 2.5 mm. This guided surgery could be used in a patient with insufficient amount of keratinized tissue around a posterior implant. For the first time, it makes it possible to anticipate, accelerate and secure the intervention, to improve the practitioner's comfort and potentially the outcomes of free gingival grafts. Further research and clinical are needed to validate this protocol and to assess its long-term impact on peri-implant health.

Interleukin-33 Deficiency Exacerbates Bone Loss Associated with Porphyromonas Gingivalis-Induced Experimental Periodontitis in Female Mice.

BACKGROUND/AIMS: Interleukin 33 (IL-33) plays a significant role in immunity but its role in bone physiology and periodontitis needs to be further investigated. The aim of this study was to decipher the contribution of IL-33 to bone homeostasis under physiological conditions, and to alveolar bone loss associated with experimental periodontitis (EP) in IL-33 knockout (KO) mice and their wildtype (WT) littermates. METHODS: The bone phenotype of IL-33 KO mice was studied in the maxilla, femur, and fifth lumbar vertebra by micro-computed tomography (micro-CT). EP was induced by a ligature soaked with the periopathogen Porphyromonas gingivalis (Pg) around a maxillary molar. Alveolar bone loss was quantified by micro-CT. The resorption parameters were assessed via toluidine blue staining on maxillary sections. In vitro osteoclastic differentiation assays using bone marrow cells were performed with or without lipopolysaccharide from Pg (LPS-Pg). RESULTS: First, we showed that under physiological conditions, IL-33 deficiency increased the trabecular bone volume/total volume ratio (BV/TV) of the maxillary bone in male and female mice, but not in the femur and fifth lumbar vertebra, suggesting an osteoprotective role for IL-33 in a site-dependent manner. The severity of EP induced by Pg-soaked ligature was increased in IL-33 KO mice but in female mice only, through an increase in the number of osteoclasts. Moreover, osteoclastic differentiation from bone marrow osteoclast progenitors in IL-33-deficient female mice is enhanced in the presence of LPS-Pg. CONCLUSION: Taken together, our data demonstrate that IL-33 plays a sex-dependent osteoprotective role both under physiological conditions and in EP with Pg.

Alendronate or Zoledronic acid do not impair wound healing after tooth extraction in postmenopausal women with osteoporosis.

BACKGROUND: Bisphosphonates (BPs) are widely used for the prevention or treatment of osteoporosis. One of the most serious complications associated with BPs is medication-related osteonecrosis of the jaw (MRONJ) but its incidence in patients with osteoporosis is very low ranging from 0.001-0.15%. A major predisposing factor for MRONJ is tooth extraction (TE). Controversies persist about the influence of current BP therapy regarding socket healing after TE. The aims of this study were to investigate prospectively, (i) alveolar bone healing, i.e., filling of the bony socket by new bone and (ii) mucosal healing, i.e., closure of the overlying mucosa, after TE in women receiving current BP therapy for the prevention or the treatment of postmenopausal osteoporosis. METHODS: Women with osteoporosis under current treatment with BPs (BP+ group) or other anti-osteoporotic medications (BP- group) undergoing single TE were included in this study. No antibiotic prophylaxis was prescribed solely for the BP therapy, but antibiotic treatment may have been required for local infectious conditions. Chlorohexidine mouthwashes were systematically prescribed in all study patients for one week after TE. New bone height (NBH) and rate of socket filling (RSF) were recorded using intraoral standardized radiographs one month and 3 months after TE (T30 and T90 respectively). The closure of the overlying mucosa was assessed by measuring the wound extent with an electronic caliper at 1 week and at 1 month after TE (T7 and T30 respectively). RESULTS: At T30, NBH was not statistically different between the BP+ and BP- groups (p = .76). At T90, more than a two-fold in NBH increase was recorded for both groups with no statistically significant difference between them (p = .76). At T30 and T90, RSF was similar in both groups (p = .58 and p = .32 respectively). More than a two-fold RSF increase was founded between T30 and T90 in both groups. No demographic or BPs-related factors were correlated with the RSF at T90. At T7, the mucosa wound extent was reduced by more than two-fold with no statistically significant difference between both groups (p = .80). At this time, mucosa healing was achieved in 11.9% of the BP+ group and 10% of the BP- group (p = .99). At T30, mucosal healing was achieved in all patients but two, and at T90 it was achieved in all patients. CONCLUSION: This study provides new insights into bone and mucosal healing in patients with osteoporosis taking BPs after TE. In this population, TE can be managed successfully with an appropriate surgical protocol and without discontinuation of BP treatment.

IL-36γ is a pivotal inflammatory player in periodontitis-associated bone loss.

Periodontitis is a prevalent chronic inflammatory disease due to the host response (IL-1ß, IL-6, TNF-α and IL-17A) to oral bacteria such as Porphyromonas gingivalis. The newer members of the IL-1 family, IL-36s (IL-36α/IL-36ß/IL-36γ/IL-36Ra/IL-38) are known to be involved in host defense against P. gingivalis in oral epithelial cells (OECs) and are considered as key inflammatory mediators in chronic diseases. The aim of this study was to investigate the potential role of IL-36s in periodontitis. We showed here that IL-36γ mRNA gingival expression is higher in periodontitis patients, whereas IL-36ß and IL-36Ra mRNA expression are lower compared to healthy controls. Interestingly, the elevated IL-36γ expression in patients is positively correlated with the RANKL/OPG ratio, an index of bone resorption. In vitro, IL-36γ expression was induced through TLR2 activation in primary OECs infected with P. gingivalis but not in gingival fibroblasts, the most widespread cell type in gingival connective tissue. In OECs, recombinant IL-36γ enhanced the expression of inflammatory cytokines (IL-1ß, IL-6, TNF-α and IL-36γ), of TLR2 and importantly, the RANKL/OPG ratio. These findings suggest that IL-36γ could be a pivotal inflammatory player in periodontitis by perpetuating gingival inflammation and its associated alveolar bone resorption and could be a relevant therapeutic target.

A nationwide survey of French dentists' knowledge and implementation of current guidelines for antibiotic prophylaxis of infective endocarditis in patients with predisposing cardiac conditions.

OBJECTIVES: To prevent infective endocarditis in patients with predisposing cardiac conditions, antibiotic prophylaxis is recommended worldwide, except in the United Kingdom. To determine the relevance of this strategy, investigating how the current guidelines are applied is crucial. The first aim of this study was to assess dentists' implementation of the current guidelines. The secondary aims were to identify relevant areas to improve the training of dentists and to determine temporal trends in practitioners' attitudes by comparison with 2 previous surveys conducted in 1991 and 2001. STUDY DESIGN: An electronic national survey was sent to the 12,000 member practitioners of the French Union for Oral Health. RESULTS: Even though 58.9% of the respondents stated that their knowledge of current guidelines was good, a scoring system showed that only 34.5% had overall knowledge of these guidelines. CONCLUSIONS: This study revealed relevant areas to improve the training of dentists, such as knowledge of some cardiac conditions, the potential side effects of the antibiotics used, and the pathogenesis of infective endocarditis. Consequently, dentists' knowledge should be improved before any conclusions can be drawn on the relevance of this antibiotic prophylaxis strategy and its influence on infective endocarditis incidence.

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

INTRODUCTION: Chronic 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-1ß, 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. OBJECTIVE: the 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 METHODS: mRNAs 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. RESULTS: IL-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. CONCLUSION: Our 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.