*These Authors contributed equally to this work. ', 'mandibular', 'foramen', 'anatomy', 'embryology', 'anthropology', and 'mental'. The reference lists of all the relevant studies and existing reviews were screened for additional relevant publications. Basing on relevant manuscripts, this short review about the anatomy, embryology and anthropology of the mandible and the mandibular foramen was written. (Folia Morphol 2013; 71, 4: 285-292)

Histone deacetylases (HDACs) are important regulators of gene expression that are aberrantly regulated in several inflammatory and infectious diseases. HDAC inhibitors (HDACi) suppress inflammatory activation of various cell types through epigenetic and non-epigenetic mechanisms, and ameliorate pathology in a mouse model of periodontitis. Activation of gingival fibroblasts (GFs) significantly contributes to the development of periodontitis and the anaerobic bacterium Porphyromonas gingivalis plays a key role in driving chronic inflammation. Here, we analyzed the role of HDACs in inflammatory responses of GFs. Pan-HDACi suberoylanilide hydroxamic acid (SAHA) and/or ITF2357 (givinostat) significantly reduced TNFα- and P. gingivalis–inducible expression and/or production of a cluster of inflammatory mediators in healthy donor GFs ( IL1B, CCL2, CCL5, CXCL10, COX2, and MMP3) without affecting cell viability. Selective inhibition of HDAC3/6, but not specific HDAC1, HDAC6, or HDAC8 inhibition, reproduced the suppressive effects of pan-HDACi on the inflammatory gene expression profile induced by TNFα and P. gingivalis, suggesting a critical role for HDAC3 in GF inflammatory activation. Consistently, silencing of HDAC3 expression with siRNA largely recapitulated the effects of HDAC3/6i on mRNA levels of inflammatory mediators in P. gingivalis–infected GFs. In contrast, P. gingivalis internalization and intracellular survival in GFs remained unaffected by HDACi. Activation of mitogen-activated protein kinases and NFκB signaling was unaffected by global or HDAC3/6-selective HDACi, and new protein synthesis was not required for gene suppression by HDACi. Finally, pan-HDACi and HDAC3/6i suppressed P. gingivalis–induced expression of IL1B, CCL2, CCL5, CXCL10, MMP1, and MMP3 in GFs from patients with periodontitis. Our results identify HDAC3 as an important regulator of inflammatory gene expression in GFs and suggest that therapeutic targeting of HDAC activity, in particular HDAC3, may be clinically beneficial in suppressing inflammation in periodontal disease.

In periodontitis, gingival fibroblasts (GFs) interact with and respond to oral pathogens, significantly contributing to perpetuation of chronic inflammation and tissue destruction. The aim of this study was to determine the usefulness of the recently released hTERT-immortalized GF (TIGF) cell line for studies of host–pathogen interactions. We show that TIGFs are unable to upregulate expression and production of interleukin (IL)-6, IL-8 and prostaglandin E2 upon infection with Porphyromonas gingivalis despite being susceptible to adhesion and invasion by this oral pathogen. In contrast, induction of inflammatory mediators in TNFα- or IL-1β-stimulated TIGFs is comparable to that observed in primary GFs. The inability of TIGFs to respond directly to P. gingivalis is caused by a specific defect in Toll-like receptor-2 (TLR2) expression, which is likely driven by TLR2 promoter hypermethylation. Consistently, TIGFs fail to upregulate inflammatory genes in response to the TLR2 agonists Pam2CSK4 and Pam3CSK4. These results identify important limitations of using TIGFs to study GF interaction with oral pathogens, though these cells may be useful for studies of TLR2-independent processes. Our observations also emphasize the importance of direct comparisons between immortalized and primary cells prior to using cell lines as models in studies of any biological processes.

CLINICAL IMAGE Strawberry gingivitis as the first manifestation of granulomatosis with polyangiitis 551in the region of the left first premolar, canine, and incisors, and on the right side, in the second incisor (FIGurE 1B). Since these lesions are most often found in granulomatosis with polyangitis (GPA; formerly known as Wegener's granulomatosis), the patient was referred to the autoimmune diseases department for further tests. No tissue biopsy was taken owing to the history of intense bleeding. Further laboratory tests revealed positive results for antineutrophil cytoplasmic antibodies (ANCA; 1:40 titer) directed against proteinase 3 (PR3, cANCA; 72 RU/ml). A computed tomography scan showed inflammatory masses in the paranasal sinuses and middle ear on the right side, and multiple nodules in both lungs. Significant conductive hearing impairment was confirmed using pure tone audiometry, while pulmonary function tests remained normal. Diagnosis of GPA was established, and treatment was initiated with methylprednisolone and cyclophosphamide (CTX) pulses. After 10 weeks of treatment (cumulative CTX dose of 4 g), the patient's general condition improved, gingival lesions completely resolved, and no further bleeding episodes from the nose and gums were reported.A 49-year-old previously healthy male patient was referred to the Institute of Dentistry, Jagiellonian University Medical College, Kraków, Poland, because of bleeding hypertrophic lesions on his gum, which developed a few weeks earlier. In the past 6 months, he had lost 7 kg without dieting, and he complained of persistent fatigue. One month before the oral manifestations, he had had several episodes of epistaxis and developed significant persistent hearing loss and tinnitus on the right side. The laboratory tests revealed lymphopenia (0.8 × 10 3 /µl; 11% of the total leukocyte count of 7.26 × 10 3 /l), an increased level of C-reactive protein (90 mg/l), and discrete proteinuria (0.09 g/l) with active urine sediment presenting as 5 to 8 red blood cells per high power field. Other kidney function parameters were within the normal range. Intraoral examination showed circumscribed, erythematous gingival enlargement typical for "strawberry-like" gingivitis. The swollen, reddened, and granular pathological lesions were located mainly on the gingiva and mucosa in the region of the right maxillary first premolar and second incisor, and the left incisors and canine (FIGurE 1A). In the mandible, the lesions were less extensive and were located FIGurE 1 A -strawberry gingivitis in the maxilla; B -strawberry gingivitis in the mandible A B

Interactions between gingival fibroblasts (GFs) and oral pathogens contribute to the chronicity of inflammation in periodontitis. Epigenetic changes in DNA methylation are involved in periodontitis pathogenesis, and recent studies indicate that DNA methyltransferase (DNMT) inhibitors may protect against epithelial barrier disruption and bone resorption. To assess the impact of DNMT inhibition on GFs, cells were cultured with decitabine (5-aza-2’-deoxycytidine, DAC) for 12 days to induce DNA hypomethylation. We observed several potentially detrimental effects of DAC on GF biological functions. First, extended treatment with DAC reduced GF proliferation and induced necrotic cell death. Second, DAC amplified Porphyromonas gingivalis- and cytokine-induced expression and secretion of the chemokine CCL20 and several matrix metalloproteinases (MMPs), including MMP1, MMP9, and MMP13. Similar pro-inflammatory effects of DAC were observed in periodontal ligament fibroblasts. Third, DAC upregulated intercellular adhesion molecule-1 (ICAM-1), which was associated with increased P. gingivalis adherence to GFs and may contribute to bacterial dissemination. Finally, analysis of DAC-induced genes identified by RNA sequencing revealed increased expression of CCL20, CCL5, CCL8, CCL13, TNF, IL1A, IL18, IL33, and CSF3, and showed that the most affected processes were related to immune and inflammatory responses. In contrast, the genes downregulated by DAC were associated with extracellular matrix and collagen fibril organization. Our observations demonstrate that studies of DNMT inhibitors provide important insights into the role of DNA methylation in cells involved in periodontitis pathogenesis. However, the therapeutic potential of hypomethylating agents in periodontal disease may be limited due to their cytotoxic effects on fibroblast populations and stimulation of pro-inflammatory pathways.