TNF ALPHA AND SEX PREVALENCE OF ORAL MANIFESTATIONS IN CHRONIC INFLAMMATORY DISEASES: IT'S COMPLICATED

Abstract

<h3>Objectives</h3> Several studies have linked chronic inflammatory conditions such as Crohn's disease (CD) or inflammatory arthritis to increased risk for periodontal disease (PD). It is attractive to attribute this to increased circulating pro-inflammatory cytokine levels such as tumor necrosis factor-alpha (TNF-α). Women show a higher incidence of CD, and women with CD have a higher risk of developing PD. How sex differences affect disease susceptibility and how this might be linked to pro-inflammatory cytokines is not well understood. The TNFΔARE (TNFΔ/WT) mouse is an established model for CD and inflammatory arthritis. The prolonged and increased TNF-α production led to spontaneous development of these 2 inflammatory diseases from a young age. Here, we used this model to test sex prevalence and the role of circulating TNF-α in the development of PD. <h3>Study Design</h3> Both male and female TNFΔARE (TNFΔ/WT) and control WT mice were analyzed at 2 and 4 months of age for changes to the temporomandibular joint (TMJ), buccal mucosa, gingival epithelium, and alveolar bone. MicroCT scans were acquired using a Milabs U-CT scanner and analyzed using Avizo 9.1.1. Oral manifestations were analyzed using histology (hematoxylin & eosin, Tartrate-resistant acid phosphatase (TRAP), Safranin O) and immunofluorescence to assess proliferation (Ki67), inflammation (CD45), and bone remodeling (Sclerostin (SOST), Receptor activator of nuclear factor kappa-B ligand (RANKL)). <h3>Results</h3> Four-month-old but not 2-month-old TNFΔ/WT showed various oral manifestations associated with arthritis (TMJ) or CD (cobblestone mucosa). No evidence of active periodontal disease was found. Four-month-old female mice showed gingival hyperplasia, severe TMJ arthritis, malocclusion, and alveolar bone loss in the absence of other signs of PD (epithelial inflammation, bleeding). Four-month-old TNFΔ/WT male mice presented TMJ arthritis, cobblestone mucosa, lack of hyperplasia but limited presence of leukocytes at the gingival epithelium, periodontal ligament, and buccal mucosa. Other signs of PD (epithelial inflammation, bleeding) were also missing. <h3>Conclusions</h3> We present strong evidence that circulating TNF-α is not sufficient to induce PD. The role of TNF-α in oral tissues is complex. TMJ arthritis and malocclusion might trigger alveolar bone loss in female TNFΔARE mice in the absence of PD. Sex-specific differences in oral manifestations (hyperplasia vs cobblestone mucosa) might be directly related to local rather than systemic differences in TNF-α.