Journal of periodontal research最新文献

In its most common form, periodontitis is viewed as a chronic immunoinflammatory disorder of the tooth supporting tissues, shaped by host-microbiome disequilibrium, exaggerated immune activation, and impaired resolution mechanisms. This review explores the periodontal battlefield through its inflammatory and immunological lens, beginning with the transformation of the lesion from silent immune surveillance to sustained inflammation, connective tissue degradation, and alveolar bone loss. The classical Page and Schroeder model is used as a foundation but reinterpreted in light of current evidence derived from advanced molecular techniques. The immunological architecture is subsequently dissected through the involvement of its principal cellular players, acting in a dynamic battleground composed of saliva, crevicular fluid, epithelial barriers, and connective tissues. On the frontlines, neutrophils act as double-edged defenders, capable of both microbial clearance and bystander tissue damage. Like macrophages and dendritic cells, they also serve as strategic sensors and shapers of immunity, bridging innate and adaptive responses. Among these, the T cell arsenal includes inflammatory subsets such as Th1, Th17, and cytotoxic cells, balanced by regulatory T cells. B lymphocytes and plasma cells emerge not only as antibody producers but also as pro-inflammatory effectors, with growing evidence implicating autoreactive subsets in tissue damage, particularly in aggressive forms of the disease. Equally critical are the structural cells: gingival fibroblasts, which transition from matrix architects to immune-active contributors under stress, and osteocytes, recognized as mechanosensitive regulators of bone turnover and immune signaling. Alongside osteoblasts and osteoclasts, these elements form a fragile yet responsive osteoimmune axis that determines the trajectory toward either tissue homeostasis or destruction. The molecular arsenal fueling this conflict-cytokines, chemokines, complement, specialized pro-resolving mediators, neuropeptides, and matrix metalloproteinases-is also examined, highlighting how its dysregulation sustains chronic inflammation and drives structural breakdown. The review also explores how this localized immune conflict echoes systemically, contributing to broader immune activation and comorbidity. By reframing periodontitis as a prototypical immune-mediated disease, this work contributes to a deeper understanding of its pathogenesis and provides a framework for future research aimed at disentangling its immunological complexity and clinical heterogeneity for targeted diagnostic strategies and immune-based therapeutics.

Aim: X-linked Hypophosphatemia (XLH), caused by PHEX mutations, hinders skeletal and dental mineralization and contributes to tooth loss. While XLH is associated with dental implant-related complications, no clinical or preclinical studies have investigated socket healing. XLH secondarily disrupts local mineral metabolism by increasing levels of the mineralization inhibitors, osteopontin (OPN) and inorganic pyrophosphate (PP_i). Tissue-nonspecific alkaline phosphatase (TNAP) promotes mineralization by dephosphorylating OPN and hydrolyzing PP_i. In this proof-of-principle study, we hypothesized that alveolar bone socket healing defects in the Hyp mouse model of XLH would be improved by exogenous TNAP.

Methods: Maxillary first molars were extracted from wild-type (WT) and Hyp mice at 6 weeks, and collagen gel ± mineral-targeted TNAP (TNAP-Fc-D₁₀; asfotase alfa) was placed in sockets. Submucosal injections of TNAP-Fc-D₁₀ or saline were delivered at 7 and 14 days post-procedure (dpp) in some mice. Maxillae were collected at 21 dpp for micro-computed tomography, histology, and RT-qPCR.

Results: Untreated Hyp mice showed impaired socket healing compared to WT mice in bone volume and density. TNAP delivered at the time of extraction was unable to improve healing in Hyp mice. However, additional local TNAP delivery increased both alveolar bone volume and density in Hyp mice. Histology indicated repeated TNAP increased both woven and mature bone in Hyp mouse sockets. Immunostaining for osteopontin and bone sialoprotein suggested partial resolution of osteoid accumulation.

Conclusion: TNAP enhanced socket healing in Hyp mice, overcoming inherent bone healing defects in XLH. These results provide new insights into bone healing with implications beyond alveolar bone in XLH.

Periodontitis is a multifactorial inflammatory disease, traditionally attributed to a bacterial biofilm. Increasing evidence indicates that viruses, especially members of the Herpesviridae family, are frequently detected in periodontal lesions and may influence disease onset and progression. This review provides an overview of viruses present in the oral cavity, including Herpesviridae, Papillomaviridae, Retroviridae, SARS-CoV-2, and emerging viral taxa such as Redondoviridae and bacteriophages, and summarizes their reported associations with periodontitis. Proposed mechanisms of viral contribution include modulation of local immune responses, facilitation of bacterial overgrowth, direct cytopathic effects on periodontal tissues, and synergistic interactions with classical periodontal pathobionts. Clinical correlations link viral load and co-infections with increased disease severity. Identification of direct causal relationships and therapeutic aspects, such as antiviral and combined antimicrobial approaches, is the subject of current research; however, clinical evidence remains limited. Overall, specific viruses show direct influence on periodontal bacterial pathogens and affect the host immune response, warranting further longitudinal and functional studies to clarify their exact role in periodontitis onset, progression, and treatment.

Objective: To answer the focused PEOS question: In animals or humans with gingival recession defects (P) what are the histological outcomes (O) of different root coverage procedures (RCPs) (E) in preclinical or clinical studies (S)?

Methods: Electronic databases (MEDLINE, EMBASE, CENTRAL) were searched for eligible studies reporting histological outcomes of RCPs in large-animal models or humans. Histomorphometric data from animal studies were summarized as pooled means (PM) for each RCP and compared between different RCPs using effect sizes (ES) based on random-effects meta-analyses.

Results: Overall, 41 preclinical (32 canine-, 5 porcine-, 4 primate-models) and 43 clinical studies, mostly case reports/series, were included. The most frequently reported RCPs were coronally advanced flaps with or without connective tissue grafts or soft-tissue substitutes. Biologicals, such as enamel matrix derivatives (EMD) or membranes, were sometimes used as adjuncts in RCPs. In human biopsies, healing following RCPs mostly occurred via the formation of long junctional epithelium (JE) and connective tissue (CT) adhesion. Some degree of periodontal regeneration was reported in half of the studies. In canine studies with experimentally created defects and limited observation times, PM of new bone, cementum, and CT attachment ranged from 0.17 to 0.50, 0.97 to 2.39, and 1.31 to 2.47, respectively. Meta-analyses revealed significantly greater new cementum with inserting fibers when using biologicals, particularly EMD (ES 0.86-0.92), or membranes (ES 0.87) as adjuncts in RCPs.

Conclusion: Healing following RCPs is generally characterized by "repair" (long JE and CT adhesion). Based on animal studies, the adjunctive use of biologicals or membranes in RCPs may enhance periodontal regeneration at least in the short term.

Trial registration: PROSPERO: CRD42024628844.

Necrotizing periodontal diseases (NPDs) are a group of clinical conditions characterized by necrosis of the gingival, periodontal, and/or oral mucosa. They include necrotizing gingivitis (NG), necrotizing periodontitis (NP), necrotizing stomatitis (NS), and noma. This study reviewed the epidemiology, etiology, and pathogenesis of these diseases. NPDs are characterized by distinct clinical features, including pain, inflammation, tissue necrosis, and unprovoked gingival bleeding, and can lead to rapid destruction of the soft and hard tissues of the periodontium and/or oral mucosa. A meta-analysis conducted in this study estimates the overall prevalence of NG was 0.04%, and is highest for Latin America (0.08%) and Asia (0.07%), among HIV-positive individuals (0.07%), and drug addicts (0.08%). The prevalence of NPD lesions is higher in young than in older age groups, particularly those with severe malnutrition. NPDs are opportunistic infections caused by the oral biofilm, in the presence of other etiological and predisposing factors. Although these causes are somewhat different from the etiological factors of periodontitis, the distinction is not well defined. Pre-existing gingival inflammation and/or periodontitis and a mixed infection are necessary causes but are not sufficient for the development of NPDs. These etiological factors, together with one or more other predisposing factors, including immunosuppression, severe psychological stress, severe malnutrition, heavy smoking, heavy alcohol consumption, uncontrolled diabetes, and HIV infection, significantly increase the risk of the development of NPDs. We propose a model that describes the causal pathway of NPDs whereby an opportunistic infection in predisposed individuals leads to microbial invasion of the gingival tissues and the development of local inflammation and tissue necrosis, which can be followed by destruction of the soft and hard oral tissues. NPDs are phenotypically distinct from conventional forms of periodontitis. However, it is unclear whether these diseases are also pathophysiologically different, as there is insufficient understanding of the underlying biological mechanisms that lead to their development.

Aim: This study aims to investigate the effect of inflammation on the senescence phenotype and osteogenic capacity of aged periodontal ligament cells (PDLCs), and to explore the regulatory role of the NF-κB signalling pathway in the osteogenesis of aged PDLCs.

Methods: Human PDLCs were isolated, and two ageing models were used: replicative senescence and etoposide treatment. The proliferation and migration of PDLCs were tested with the cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, and scratch test. Proinflammatory cytokine levels were tested using enzyme-linked immunosorbent assay and real time-quantitative polymerase chain reaction. Osteogenic differentiation was evaluated through alkaline phosphatase activity, Alizarin Red S staining, and calcium quantification. Expression levels of nuclear factor kappa-B (NF-κB) and c-JUN pathway-related proteins were analyzed through Western blotting.

Results: Inflammatory stimulation enhanced the senescence phenotype in both young and aged PDLCs and inhibited osteogenic differentiation in aged PDLCs. During cellular ageing, NF-κB signalling downregulated the osteogenic differentiation of PDLCs by suppressing forkhead box O3a (FOXO3a) and c-JUN. Conversely, under exogenous inflammatory stimulation, NF-κB signalling inhibited osteogenesis by promoting FOXO3a phosphorylation and increasing c-JUN expression, with p21 exerting a synergistic inhibitory effect on osteogenic differentiation in aged PDLCs.

Conclusion: Inflammation aggravates cellular senescence and suppresses osteogenic differentiation in aged PDLCs through the NF-κB/FOXO3a/c-JUN signalling pathway.

This paper provides a detailed analysis of systemic diseases associated with periodontal tissue loss, focusing on their clinical presentation and etiopathogenesis. It also introduces a framework for categorizing these diseases according to their principal pathological pathways and their periodontal effects. Periodontitis arises from a disruption of host-microbe homeostasis, which leads to a dysbiotic microbiota, chronic inflammation, and subsequent periodontal tissue loss. Complex systemic diseases, particularly those causing systemic inflammation or having an autoimmune component (e.g., diabetes mellitus, osteoporosis, arthritis, and inflammatory bowel disease), can exacerbate pre-existing periodontal inflammation and cause further tissue loss. As their inflammatory and pathological pathways are intertwined with periodontitis, their periodontal manifestations are not considered distinct forms of the disease. In contrast, other systemic diseases disrupt host-microbe homeostasis by causing specific defects in the immune response, whereas others impair tissue metabolism or disrupt the physiology and integrity of epithelial and connective tissues. These diseases can lead to significant periodontal destruction and are considered distinct forms of periodontitis. Examples include Down syndrome, leukocyte adhesion deficiency syndromes, Papillon-Lefèvre syndrome, Haim-Munk syndrome, Chediak-Higashi syndrome, neutropenia, primary immunodeficiency diseases, Cohen syndrome, glycogen storage diseases, Gaucher disease, hypophosphatasia, hypophosphatemic rickets, Hajdu-Cheney syndrome, epidermolysis bullosa, hypoplasminogenemia, and Ehlers-Danlos syndrome. A third category encompasses diseases that induce periodontal tissue loss through mechanisms independent of periodontitis. Examples of this group include Langerhans cell histiocytosis, hyperparathyroidism, and giant cell granulomas. In conclusion, systemic diseases contribute to periodontal tissue loss through overlapping inflammatory pathways, immune dysfunction, or other independent mechanisms. Grouping these diseases by their primary pathological pathways offers a clearer understanding of their effect on periodontal health. This framework may also help direct research toward uncovering shared and unique mechanisms of systemic disease-related periodontal pathology, potentially leading to more targeted therapies and improved disease management.

Epigenetic modifications regulate gene activity in response to environmental and intrinsic factors, offering potential as reversible biomarkers and therapeutic targets. Their role in periodontitis, however, remains insufficiently defined. This review critically evaluates current evidence on epigenetic mechanisms in periodontitis, emphasizing methodological challenges such as cell-type heterogeneity, small sample sizes, and the detection of meaningful tissue-specific changes. Chronic inflammation and environmental exposures, notably tobacco smoke, induce stable, gene-specific DNA methylation changes in gingival tissues. Key epigenetic alterations have been identified in several genes such as CYP1B1, AHRR, ROBO2, and PTP4A3, which are implicated in detoxification, epithelial repair, and immune responses. These modifications are often cell-type-specific. Despite their biological relevance, most studies are limited by small cohorts and mixed-cell population analyses, complicating interpretation. DNA CpG methylation is the primary focus, given its chemical stability and established analytical platforms, while histone and RNA modifications remain understudied due to technical challenges. Epigenetic regulation appears to contribute to the pathogenesis of periodontitis, particularly in response to persistent environmental and inflammatory stimuli. However, clinical translation is constrained by methodological limitations. Future research must incorporate larger sample sizes, address cellular heterogeneity, and investigate the reversibility of epigenetic marks following periodontal therapy or elimination of harmful exposures. Advancing tissue-specific epigenetic profiling may enhance early detection, risk stratification, and personalized prevention strategies. Rigorous study designs and standardized methodologies will be essential to realizing the clinical potential of epigenetic research in periodontal disease.