osteoprotegerin and Periodontal-Diseases

Periodontal disease is characterized by inflammation of the periodontal tissue and subsequent destruction of the alveolar bone. It is one of the most common infectious diseases in humans, being the leading cause of tooth loss in adults. Recently, it has been shown that the receptor activator of NF-κB ligand (RANKL) produced by osteoblasts and periodontal ligament fibroblasts critically contributes to the bone destruction caused by periodontal disease. Activation of the immune system plays an important role in the induction of RANKL during periodontal inflammation. Here we discuss the molecular mechanisms of periodontal bone destruction by focusing on the osteoimmune molecule RANKL.

Topics: Humans; Inflammation; Osteoclasts; Osteoprotegerin; Periodontal Diseases; Periodontal Ligament; Periodontitis; RANK Ligand

MicroRNAs (miRNAs) bind at the 3'UTR of their target mRNA to induce gene silencing. Through this mechanism, number of biological pathways implicated in developmental, physiological, and pathological processes, have been frequently found to involve miRNA functions. MiRNA functions in bone metabolism have also been reported, especially in association with receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis. Expression of RANKL has been related to several inflammatory mediators, and thus some miRNAs may be implicated in the regulatory mechanism of inflammatory-induced RANKL expression as shown in periodontal resident cells such as gingival fibroblasts or periodontal ligament cells. This review aims to review the current miRNA research relating periodontal tissue and its relevance in periodontal inflammation. In miRNA profiling studies of tissues isolated from individuals with periodontal disease, miR-223 has been consistently identified as a potential candidate miRNA to be further investigated in periodontitis-related processes. Although these studies point to an important role of miRNA-mediated epigenetic changes in tissue inflammation and alveolar bone loss, further investigation is still required to determine the function of miRNAs in the complex processes of periodontal tissue homeostasis and pathogenesis. Knowledge gained from future studies will be beneficial in developing alternative therapeutic approaches, especially ones that use miRNA delivery systems to treat periodontal disease.

Topics: Alveolar Bone Loss; Biomarkers; Bone Remodeling; Humans; Inflammation Mediators; MicroRNAs; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Vitamin D has been shown to regulate musculoskeletal health by mediating calcium absorption and mineral homeostasis. Evidence has demonstrated that vitamin D deficiency may place subjects at risk for not only low mineral bone density/osteoporosis and osteopenia but also infectious and chronic inflammatory diseases. Studies have shown an association between alveolar bone density, osteoporosis and tooth loss and suggest that low bone mass may be a risk factor for periodontal disease. Several recent reports demonstrate a significant association between periodontal health and the intake of vitamin D. An emerging hypothesis is that vitamin D may be beneficial for oral health, not only for its direct effect on bone metabolism but also due to its ability to function as an anti-inflammatory agent and stimulate the production of anti-microbial peptides.

Topics: Antimicrobial Cationic Peptides; Bone Remodeling; Calcium; Humans; Immunity, Innate; Inflammation; Oral Health; Osteoblasts; Osteopontin; Osteoporosis; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Rickets; Vitamin D

Inflammation and bone loss are hallmarks of periodontal disease (PD). The question is how the former leads to the latter. Accumulated evidence demonstrates that PD involves bacterially derived factors and antigens that stimulate a local inflammatory reaction and activation of the innate immune system. Proinflammatory molecules and cytokine networks play essential roles in this process. Interleukin-1 and tumor necrosis factor-alpha seem to be primary molecules that, in turn, influence cells in the lesion. Antigen-stimulated lymphocytes (B and T cells) also seem to be important. Eventually, a cascade of events leads to osteoclastogenesis and subsequent bone loss via the receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) axis. This axis and its regulation are not unique to PD but rather are critical for pathologic lesions involving chronic inflammation. Multiple lines of evidence in models of PD clearly indicate that increases in RANKL mRNA expression and protein production increase the RANKL/OPG ratio and stimulate the differentiation of macrophage precursor cells into osteoclasts. They also stimulate the maturation and survival of the osteoclast, leading to bone loss. OPG mRNA expression and protein production do not generally seem to be increased in the periodontitis lesion. Studies of RANKL and OPG transgenic and knockout animals provide further support for the involvement of these molecules in the tissue loss observed in PD. Ironically, periodontal practitioners have focused on the bacterial etiology of PD and believed that plaque removal was aimed at eliminating specific bacteria or bacterial complexes. However, it seems that the reduction of inflammation and attenuation of the host's immune reaction to the microbial plaque, eventually leading to a decrease in the ratio of RANKL/OPG and a decrease in associated bone loss, are the actual and desired outcomes of periodontal therapy. Future therapeutic options are likely to have regulation of the RANK-RANKL-OPG axis as their goal.

Topics: Alveolar Bone Loss; Antigens; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Osteoclasts; Osteoprotegerin; Periodontal Diseases; Periodontitis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Chronic diseases, such as periodontal disease (PD) and rheumatoid arthritis (RA), are characterized by a robust immune response resulting in unresolved inflammation. Inflammation is mediated by proinflammatory cytokines; recently, a novel subset of T-helper (Th) cells was identified that plays a crucial role in inflammation and autoimmune disease. This population secretes several proinflammatory cytokines, including the novel cytokine interleukin (IL)-17, and, hence, has been termed "Th17." Inflammatory cytokines are implicated in the progression of localized chronic infections, such as PD, and in serious systemic pathologies, such as diabetes, chronic obstructive pulmonary disease, and cardiovascular disease. IL-17 mediates inflammation through a receptor (IL-17R) composed of two subunits, IL-17RA and IL-17RC. Drugs that antagonize inflammatory cytokines are used therapeutically to downregulate immune-mediated pathology in conditions such as RA, although not all patients respond well to this approach. Therefore, identification of potential novel therapeutic targets, such as the IL-17 signaling complex, may be clinically relevant for mitigating inflammatory pathology. However, the manner in which such a therapeutic may influence the onset and progression of PD is poorly understood. Therapeutics that antagonize inflammatory cytokines ameliorate inflammation and bone loss and may have broader implications for individuals with systemic diseases in which inflammation and autoimmunity predominate.

Topics: Alveolar Bone Loss; Animals; Autoimmune Diseases; Autoimmunity; Humans; Inflammation; Interleukin-17; Mandibular Diseases; Maxillary Diseases; Mice; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Receptors, Interleukin-17; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory

Osteoclasts are primary cells for physiological and pathological bone resorption, and receptor activator of nuclear factor-kappaB ligand (RANKL) is critically involved in the differentiation, activation, and survival of these cells. Recently, therapeutics for pathological bone destruction targeting RANKL pathways has attracted a great deal of attention. Herein, we review the recent advances in the research on osteoclast biology and discuss the advantages and disadvantages of anti-RANKL therapies.

Topics: Animals; Apoptosis; Arthritis, Rheumatoid; Bone Resorption; Carrier Proteins; Cell Differentiation; Glycoproteins; Humans; Membrane Glycoproteins; NF-kappa B; Osteoclasts; Osteoporosis; Osteoprotegerin; Periodontal Diseases; Proto-Oncogene Proteins c-bcl-2; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Signal Transduction; TNF Receptor-Associated Factor 6

Periodontal disease (PD) and rheumatoid arthritis (RA) are bone pathologies mediated through immuno-inflammatory mechanisms. The aim of this study was to investigate the serum markers osteopontin (OPN), tumor necrosis factor receptors 1 (TNFR1) and 2 (TNFR2) receptor activator of nuclear factor-kappa B ligand (RANKL) and RANKL/ osteoprotegerin (OPG) ratio and compare them in PD and RA groups.. RA (with PD = 19 and without PD = 19), PD (n = 38) and 14 healthy subjects underwent bleeding on probing (BOP) and probing pocket depth (PPD) measurement. PD was defined as PPD measuring ≥5mm registered in ≥3 sites. Marginal bone loss (MBL) for premolars and molars was measured on digital panoramic radiographs. Serum samples were collected from all subjects. OPN, TNFR1, TNFR2 and RANKL were measured by enzyme-linked immunosorbent assays (ELISAs). OPG was measured as part of a multiplex proximity extension assay (PEA).. OPN, TNFR1, TNFR2 and RANKL serum levels were the highest in the RA group with PD, while the RA group without PD were comparable to PD subjects only. The RANKL/OPG ratios were comparable between PD group and both RA groups with (p = 0.051) and without PD (p = 0.37). Serum RANKL levels were associated with MBL (p = 0.008) and PPD ≥ 5mm (p = 0.01).. Peripheral osteoclastogenesis is a feature of periodontal disease with systemic levels of osteoclastogenic markers comparable to the effects observed in rheumatoid arthritis.

Topics: Adult; Arthritis, Rheumatoid; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II

Evidence has suggested that periodontal disease is associated with an increased risk of various adverse pregnancy and birth outcomes. However, several large clinical randomized controlled trials failed to demonstrate periodontal therapy during pregnancy reduced the incidence of adverse pregnancy and birth outcomes. It has been suggested that the pre-conception period may be an optimal period for periodontal disease treatment rather than during pregnancy. To date, no randomized controlled trial (RCT) has examined if treating periodontal disease before pregnancy reduces adverse birth outcomes. This study aims to examine if the pre-conception treatment of periodontal disease will lead to improved periodontal status during late pregnancy and subsequent birth outcomes.. A sample of 470 (235 in each arm of the study) pre-conception women who plan to conceive within one year and with periodontal disease will be recruited for the study. All participants will be randomly allocated to the intervention or control group. The intervention group will receive free therapy including dental scaling and root planning (the standard therapy), supragingival prophylaxis, and oral hygiene education. The control group will only receive supragingival prophylaxis and oral hygiene education. Women will be followed throughout their pregnancy and then to childbirth. The main outcomes include periodontal disease status in late pregnancy and birth outcomes measured such as mean birth weight (grams), and mean gestational age (weeks). Periodontal disease will be diagnosed through a dental examination by measuring probing depth, clinical attachment loss and percentage of bleeding on probing (BOP) between gestational age of 32 and 36 weeks. Local and systemic inflammatory mediators are also included as main outcomes.. This will be the first RCT to test whether treating periodontal disease among pre-conception women reduces periodontal disease during pregnancy and prevents adverse birth outcomes. If the effect of pre-pregnancy periodontal treatment is confirmed, this intervention could be recommended for application in low- or middle-income countries to improve both oral health and maternal and child health.. This trial is registered with Chinese Clinical Trial Registry (ChiCTR): ChiCTR-TRC-12001913.

Topics: Adolescent; Adult; Aspartate Aminotransferases; Birth Weight; Dental Scaling; Dinoprostone; Female; Gestational Age; Glucuronidase; Humans; Interleukin-1beta; Interleukin-6; Matrix Metalloproteinase 8; Oral Hygiene; Osteoprotegerin; Patient Education as Topic; Periodontal Diseases; Preconception Care; Pregnancy; Research Design; Root Planing; Saliva; Tumor Necrosis Factor-alpha; Young Adult

Alveolar bone resorption results from the inflammatory response to periodontal pathogens. Systemic diseases that affect the host response, such as type 1 diabetes mellitus (DM1), can potentiate the severity of periodontal disease (PD) and accelerate bone resorption. However, the biological mechanisms by which DM1 modulates PD are not fully understood. The aim of this study was to determine the influence of DM1 on alveolar bone resorption and to evaluate the role of receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) in osteoclastogenesis in rats. PD was induced by means of ligature in nondiabetic and in streptozotocyn-induced DM1 rats. Morphological and morphometric analyses, stereology and osteoclast counting were performed. RANKL and OPG mRNA levels, protein content, and location were determined. PD caused alveolar bone resorption, increased the number of osteoclasts in the alveolar bone crest and also promoted changes in RANKL/OPG mRNA expression. DM1 alone showed alveolar bone destruction and an increased number of osteoclasts at the periapical and furcal regions. DM1 exacerbated these characteristics, with a greater impact on bone structure, resulting in a low OPG content and a higher RANKL/OPG ratio, which correlated with prominent osteoclastogenesis. This work demonstrates that the effects of PD and DM1 enhance bone destruction, confirms the importance of the RANKL signaling pathway in bone destruction in DM1 in animal models and suggests the existence of alternative mechanisms potentiating bone degradation in PD.

Topics: Alveolar Bone Loss; Animals; Bone Resorption; Diabetes Mellitus, Type 1; Humans; Immunohistochemistry; Male; Osteoclasts; Osteoprotegerin; Periodontal Diseases; Rats; Rats, Wistar

Periodontitis is the major cause of tooth loss in adults and is linked to systemic illnesses, such as cardiovascular disease and stroke. The development of rapid point-of-care (POC) chairside diagnostics has the potential for the early detection of periodontal infection and progression to identify incipient disease and reduce health care costs. However, validation of effective diagnostics requires the identification and verification of biomarkers correlated with disease progression. This clinical study sought to determine the ability of putative host- and microbially derived biomarkers to identify periodontal disease status from whole saliva and plaque biofilm.. One hundred human subjects were equally recruited into a healthy/gingivitis group or a periodontitis population. Whole saliva was collected from all subjects and analyzed using antibody arrays to measure the levels of multiple proinflammatory cytokines and bone resorptive/turnover markers.. Salivary biomarker data were correlated to comprehensive clinical, radiographic, and microbial plaque biofilm levels measured by quantitative polymerase chain reaction (qPCR) for the generation of models for periodontal disease identification. Significantly elevated levels of matrix metalloproteinase (MMP)-8 and -9 were found in subjects with advanced periodontitis with Random Forest importance scores of 7.1 and 5.1, respectively. The generation of receiver operating characteristic curves demonstrated that permutations of salivary biomarkers and pathogen biofilm values augmented the prediction of disease category. Multiple combinations of salivary biomarkers (especially MMP-8 and -9 and osteoprotegerin) combined with red-complex anaerobic periodontal pathogens (such as Porphyromonas gingivalis or Treponema denticola) provided highly accurate predictions of periodontal disease category. Elevated salivary MMP-8 and T. denticola biofilm levels displayed robust combinatorial characteristics in predicting periodontal disease severity (area under the curve = 0.88; odds ratio = 24.6; 95% confidence interval: 5.2 to 116.5).. Using qPCR and sensitive immunoassays, we identified host- and bacterially derived biomarkers correlated with periodontal disease. This approach offers significant potential for the discovery of biomarker signatures useful in the development of rapid POC chairside diagnostics for oral and systemic diseases. Studies are ongoing to apply this approach to the longitudinal predictions of disease activity.

Topics: Adult; Aged; Alveolar Bone Loss; Bacteria; Biofilms; Biomarkers; Chronic Periodontitis; Dental Plaque; Disease Progression; Female; Gingivitis; Humans; Interferon-gamma; Interleukins; Leukocyte L1 Antigen Complex; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Middle Aged; Osteoprotegerin; Periodontal Attachment Loss; Periodontal Diseases; Periodontium; Porphyromonas gingivalis; Saliva; Treponema denticola; Tumor Necrosis Factor-alpha; Young Adult

The dependence between gingival crevicular fluid (GCF) of Interleukin-34 (IL-34) level and Receptor activator of nuclear factor -kB ligand/ osteoprotegerin (RANKL/OPG) ratio in the severity of periodontitis might reveal an unknown pathway of diseases with bone destruction. There is no study about the evaluation of IL-34 levels together with GCF RANKL and OPG levels in periodontitis patients before and after non-surgical periodontal treatment (NSPT). The objectives of this research were to investigate changes in the levels and relative ratios of IL-34, OPG, and RANKL in the GCF of patients with periodontitis before and after NSPT.. 20 healthy participants (CTRL), 20 patients with stage 3-grade B periodontitis and 20 with stage 3-grade C periodontitis were recruited. GCF and clinical periodontal recordings were investigated at the baseline and 6 weeks after NSPT. Enzyme-linked immunosorbent assay (ELISA) were used for quantifying of GCF IL-34, RANKL and OPG levels and their relative ratios were calculated.. Greater values for GCF IL-34 and RANKL levels were found in the both of periodontitis groups than in CTRL group at baseline, whereas GCF OPG levels were statistically lower at baseline (P < 0.05). GCF IL-34 and RANKL levels decreased in the 6th week after NSPT in the both periodontitis groups, while the concentration OPG levels statistically increased (P < 0.05). Significantly positive correlations among the IL-34 with RANKL, sampled-site clinical attachment level (CAL), and gingival index (GI), whereas negative correlation with OPG were reported (P < 0.05).. GCF IL-34 levels was high in patients with periodontitis and decreased after NSPT and its levels showed positive correlations with RANKL/OPG ratio levels CAL and GI. Determining of IL-34 levels together with RANKL/OPG ratio in GCF may therefore be valuable in detecting high risk individuals with periodontitis patients.

Topics: Adult; Chronic Periodontitis; Female; Gingival Crevicular Fluid; Humans; Interleukins; Male; NF-kappa B; Osteoprotegerin; Periodontal Diseases; Periodontal Index; RANK Ligand; Young Adult

Periodontitis, an infective disease caused by oral pathogens and the intrinsic aging process, results in the destruction of periodontal tissues and the loss of alveolar bone. This study investigated whether

Topics: Alveolar Bone Loss; Animals; Cathepsin K; Collagen Type I; Collagen Type I, alpha 1 Chain; Gingiva; Inflammation; Interleukin-1beta; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 8; Models, Animal; NF-kappa B; Osteoporosis; Osteoprotegerin; Periodontal Diseases; Periodontitis; Plant Extracts; Proto-Oncogene Proteins c-fos; RANK Ligand; Rats; Rats, Inbred F344; RNA, Messenger; Tartrate-Resistant Acid Phosphatase; Transcription Factors; X-Ray Microtomography; Zingiberaceae

Periodontitis, an inflammatory disease of the gingival tissue, triggered by microbial-derived elements, such as lipopolysaccharide (LPS), collapses the periodontal tissues and resorbs the alveolar bone. This study evaluated the inhibitory effects of standardized Boesenbergia pandurata extract (BPE) and panduratin A (PAN) on periodontitis-induced inflammation and alveolar bone loss. Sprague-Dawley rats with LPS-induced periodontitis were orally administered BPE (50 and 200 mg/kg/day) and PAN (20 mg/kg/day) for 8 days. Histological analysis revealed that BPE- and PAN-administered groups showed decreased cell infiltration and alveolar bone resorption. Furthermore, the BPE and PAN significantly alleviated the mRNA and protein expression levels of nuclear factor kappa B (NF-κB), interleukin-1β, matrix metalloproteinase (MMP)-2, and MMP-8. BPE and PAN also inhibited the expression of nuclear factor of activated T cells, cytoplasmic 1, c-Fos, and ostoclastogenesis-related enzymes, including cathepsin K and tartrate-resistant acid phosphatase (ALP). BPE and PAN not only upregulated the osteoblastogenesis-associated markers, such as collagen type I (COL1A1) and ALP, but also increased the ratio of osteoprotegerin to receptor activator of NF-κB ligand. Collectively, BPE and PAN efficiently prevent destruction of periodontal tissues and stimulating the loss of alveolar bone tissues, strongly indicative of their potential as natural antiperiodontitis agents.

Topics: Alveolar Bone Loss; Animals; Chalcones; Collagen Type I; Humans; Interleukin-1beta; Lipopolysaccharides; Male; Matrix Metalloproteinase 2; NF-kappa B; Osteoprotegerin; Periodontal Diseases; Plant Extracts; Rats; Rats, Sprague-Dawley; Zingiberaceae

Increased level of proinflammatory cytokine interleukin (IL)-12 correlates with the severity of periodontitis. Yet, a possible role of IL-12 in periodontal disease has not been clarified. The aim of this study is to investigate whether IL-12 affects expression of receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL), a potent osteoclast-stimulating factor, by human periodontal ligament (hPDL) cells.. To determine the effect of IL-12, hPDL cells were incubated with recombinant human IL-12 (p70) in a dose- (0 to 10 ng/mL) and time-dependent manner. Expression of RANKL was evaluated at mRNA and protein levels. Underlying signaling pathways of IL-12 were determined by using specific inhibitors.. Under the influence of IL-12, hPDL cells expressed significantly higher levels of RANKL. Expression was mediated by signal transducer and activator of transcription 4 and NF-κB signaling pathways. Conditioned medium of IL-12-incubated cells proved to contain molecule(s) that induced RANKL expression. Addition of suramin (G protein-coupled receptor inhibitor) and ethylene glycol tetraacetic acid (calcium chelator) suggested existence of intermediate molecule(s) that could activate heterotrimeric G protein signaling in a calcium-dependent pathway.. Expression of RANKL by hPDL cells significantly increased after IL-12 treatment. Therefore, this study supports a close interrelationship between immune and skeletal systems and suggests an osteolytic role of IL-12 in pathogenesis of periodontal disease.

Topics: Adult; Cells, Cultured; Female; Humans; Interleukin-12; Male; NF-kappa B; Osteoprotegerin; Periodontal Diseases; Periodontal Ligament; RANK Ligand; Receptors, Interleukin-12; RNA, Messenger; Young Adult

Porphyromonas gingivalis is involved in the pathogenesis of chronic inflammatory periodontal disease. Recent studies have suggested that the NLRP3 inflammasome plays an important role in the development of chronic inflammation. We investigated a possible association between the inflammasome in gingival inflammation and bone loss induced by P. gingivalis infection using NLRP3-deficient mice.. Wild-type and NLRP3-deficient mice were injected orally with P. gingivalis. We assessed alveolar bone loss, expression of pro-interleukin (IL)-1β, pro-IL-18, receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) in gingival tissue, as well as IL-1β, IL-18, and IL-6 production and caspase-1 activity in peritoneal macrophages.. Porphyromonas gingivalis challenge significantly increased alveolar bone loss; gingival gene expression of pro-IL-1β, pro-IL-18, and RANKL; production of IL-1β, IL-18, and IL-6; and caspase-1 activity in peritoneal macrophages of wild-type mice, but did not affect NLRP3-deficient mice. Meanwhile, OPG mRNA expression in gingival tissue and peritoneal IL-6 production were significantly higher in NLRP3-knockout mice.. Porphyromonas gingivalis activated innate immune cells via the NLRP3 inflammasome. These results suggest that the NLRP3 inflammasome, followed by a response from the IL-1 family, is critical in periodontal disease induced by wild-type P. gingivalis challenge via sustained inflammation.

Topics: Alveolar Bone Loss; Animals; Bone and Bones; Cytokines; Gingiva; Inflammasomes; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Osteoprotegerin; Periodontal Diseases; Porphyromonas gingivalis; RANK Ligand

Recent studies point to the clinical utility of using peri-implant sulcular fluid (PISF) as a valuable diagnostic aid for monitoring peri-implant tissue health. The objectives of this study are to determine the levels of key biomarkers in PISF in periodontal maintenance participants and compare them with their corresponding levels in gingival crevicular fluid (GCF) obtained from the same participants.. PISF and GCF were collected from an implant and a contralateral natural tooth after the clinical examination of 73 participants. The levels of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17A, tumor necrosis factor (TNF)-α, C-reactive protein, osteoprotegerin, leptin, and adiponectin were determined using multiplex proteomic immunoassays. The correlation of biomarker concentrations between GCF versus PISF, within GCF or PISF, and with several covariates (age, brushing frequency, days since professional cleaning, probing depth [PD], and plaque index) were also determined.. Significantly higher levels of IL-17A (P = 0.02) and TNF-α (P = 0.03) were noted in PISF when compared with their levels in GCF. Significant positive correlations were noted between the concentrations of cytokines in PISF versus their levels in GCF. Among the covariates, a significant positive correlation was noted between mean PDs around implants and levels of IL-1β (P <0.05) and IL-8 (P <0.05) in PISF.. The results of this study point to the differential expression of specific biomarkers in GCF versus their levels in PISF in periodontal maintenance patients, which is critical information before establishing PISF as a diagnostic fluid to monitor peri-implant health.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Dental Implants; Dental Plaque Index; Dental Prophylaxis; Female; Gingival Crevicular Fluid; Humans; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-1alpha; Interleukin-1beta; Interleukin-6; Interleukin-8; Leptin; Male; Middle Aged; Osteoprotegerin; Periodontal Diseases; Periodontal Pocket; Toothbrushing; Tumor Necrosis Factor-alpha; Young Adult

The objective of the present study was to evaluate the capacity of a tissue-engineered complex of human osteoprotegerin (hOPG)-transfected periodontal ligament stem cells (PDLSCs) seeding on beta-tricalcium phosphate (β-TCP) to regenerate alveolar bone defects in New Zealand rabbits.. PDLSCs were isolated from rabbit periodontal ligament tissues and expanded in vitro to enrich PDLSC numbers, and their proliferative activities and differentiation capability were evaluated under specific induction conditions. Lentiviral vector containing hOPG and enhanced green fluorescent protein (EGFP) was constructed by using Gateway technology and transfected into rabbit PDLSCs. The expression of hOPG was determined with quantitative real-time reverse transcription-polymerase chain reaction and Western blot. The PDLSCs with or without engineered hOPG were seeded on β-TCP scaffolds prior to transplantation. Morphological characterization of cells and materials was done by scanning electron microscope. Twenty rabbits with alveolar bone defects were randomly allocated into four groups and transplanted with β-TCP, PDLSCs/β-TCP, and hOPG-transfected PDLSCs/β-TCP or were left untreated as a control. Animals were sacrificed 12 weeks after operation for histological observation and histomorphometric analysis.. PDLSCs expressed STRO-1 and vementin and favored osteogenesis and adipogenesis in conditioned media. Expressions of hOPG were significantly upregulated after transfection of the lentiviral vector into PDLSCs. PDLSCs attached and spread well on β-TCP, and there was no significant difference in growth of PDLSCs on β-TCP between the hOPG transfection group and the non-transfection group. The histological observation and histomorphometric analysis showed that the hOPG-transfected PDLSCs/β-TCP complex exhibited an earlier mineralization and more bone formation inside the scaffold than control, β-TCP, and PDLSCs/β-TCP complexes. Implantation of hOPG-transfected PDLSCs contributed to new bone formation as determined by EGFP gene expression under circularly polarized light microscopy.. The present study demonstrated the feasibility of β-TCP scaffolds for primary PDLSC culture and expression of hOPG gene in vitro and in vivo, and hOPG-transfected PDLSCs could serve as a potential cell source for periodontal bone regeneration, which may shed light on the potential of systemic hOPG gene therapy in combination with PDLSC tissue engineering as a good candidate in periodontal tissue engineering for alveolar bone regeneration.

Topics: Alveolar Bone Loss; Animals; Antigens, Surface; Bone Regeneration; Calcium Phosphates; Cell Differentiation; Cells, Cultured; Green Fluorescent Proteins; Guided Tissue Regeneration, Periodontal; HEK293 Cells; Humans; Male; Osteogenesis; Osteoprotegerin; Periodontal Diseases; Periodontal Ligament; Periodontium; Rabbits; Stem Cell Transplantation; Stem Cells; Tissue Engineering; Tissue Scaffolds

The objective of this study was to assess the effects of oral ingestion of β-glucans isolated from Saccharomyces cereviseae on the metabolic profile, expression of gingival inflammatory markers and amount of alveolar bone loss in diabetic rats with periodontal disease. Diabetes mellitus was induced in 48 Wistar rats by intraperitoneal injection of streptozotocin (80 mg/kg). After confirming the diabetes diagnosis, the animals were treated with β-glucans (by gavage) for 28 days. On the 14th day of this period, periodontal disease was induced using a ligature protocol. β-glucans reduced the amount of alveolar bone loss in animals with periodontal disease in both the diabetic and non-diabetic groups (p < 0.05). β-glucans reduced blood glucose, cholesterol and triacylglycerol levels in diabetic animals, both with and without periodontal disease (p < 0.05). Furthermore, treatment with β-glucans reduced the expression of cyclooxygenase-2 and receptor activator of nuclear factor kappa-B ligand and increased osteoprotegerin expression in animals with diabetes and periodontal disease (p < 0.05). It was concluded that treatment with β-glucans has beneficial metabolic and periodontal effects in diabetic rats with periodontal disease.

Topics: Alveolar Bone Loss; Animals; beta-Glucans; Blood Glucose; Cholesterol; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Disease Models, Animal; Gingiva; Male; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Rats; Rats, Wistar; Saccharomyces cerevisiae; Streptozocin; Triglycerides

Chronic periodontal disease is characterized by alveolar bone loss and inflammatory changes. Reveromycin A (RMA) was recently developed and is a unique agent for inhibiting osteoclast activity. This study analysed the effects of RMA in an experimental mouse model of periodontitis involving osteoprotegerin (OPG)-knockout mice, specifically, whether it could control osteoclasts and reduce inflammation in periodontal tissue. We examined wild-type (WT) and OPG knockout mice (OPG KO) ligated with wire around contact points on the left first and second molars. RMA was administered twice a day to half of the mice. Using micro-computed tomography, we measured the volume of alveolar bone loss between the first and second molars, and also performed histological analysis. The OPG KO RMA+ group had significantly decreased osteoclast counts, alveolar bone loss, attachment loss, and inflammatory cytokine expression 8 weeks after ligation. Thus, RMA may reduce alveolar bone loss and inflamed periodontal tissues in patients with periodontitis.

Topics: Alveolar Bone Loss; Animals; Cytokines; Disease Models, Animal; Inflammation Mediators; Male; Mice; Mice, Knockout; Osteoclasts; Osteoprotegerin; Periodontal Diseases; Pyrans; Spiro Compounds; X-Ray Microtomography

The Receptor activator of nuclear factor-kappa B ligand (RANKL)/RANK/Osteoprotegerine (OPG) system has been proposed as essential for osteoclast biology and identified as key part in regulating the physiology and pathology of the skeletal system. The study of the RANKL/RANK/OPG system has increased the understanding of the mechanisms involved in the bone remodeling process, especially in postmenopausal osteoporosis and periodontal disease. Bisphosphonates have become the mainstay of the treatment and prevention of post-menopausal osteoporosis. They inhibit the formation and dissolution of calcium phosphate crystals in bone and also osteoclasts, thus reducing bone turnover.Current investigations relate osteoporosis with the appearance and progression of periodontal disease. Although the etiology of both is different, the bone loss present in both shares several characteristics. Thus, therapy used for osteoporosis can be considered of value in the treatment of periodontal disease. The aim of this study was to evaluate the levels of RANKL, OPG and their relationship in gingival crevicular fluid (GCF) in patients with periodontal disease and postmenopausal osteoporosis/ osteopenia in relation to consumption of bisphosphonates. We studied 66 periodontal active sites obtained from 17 post- menopausal women patients aged between 45-70 years old with osteoporosis/osteopenia and periodontal disease. GCF samples were collected using sterile filter paper strips. To determine the concentration of RANKL and OPG, a commercial ELISA assay was used. The values of RANKL, OPG and their ratio (RANKL/ OPG) were compared with Mann-Whitney U Test. The values of RANKL, OPG and their ratio obtained in patients with osteoporosis/osteopenia and periodontal disease with or without bisphosphonates treatment showed no differences. Bisphosphonates do not alter the concentration of RANKL and OPG and their ratio in the GCF of patients with osteoporosis/ osteopenia and periodontal disease, probably because these cytokines may not be the main target of bisphosphonates to inhibit bone resorption in periodontal disease.. El sistema: Receptor activador del factor nuclear kappa-B ligando (RANKL)/RANK/Osteoprotegerina (OPG) ha sido propuestos como esencial para la biología osteoclástica, ya que ha sido identificado como participante clave en la regulación fisiológica y patológica del sistema óseo. El estudio del sistema RANKL-RANK-OPG ha facilitado la comprensión de los mecanismos intervinientes en el proceso de remodela- ción ósea, especialmente en la osteoporosis post-menopáusica y la enfermedad periodontal. Los bisfosfonatos se han convertido en el pilar principal del tratamiento y prevención de la osteoporosis post-menopáusica. Ellos inhiben la formación y disolución de los cristales de fosfato de calcio en el hueso y también inhiben a los osteoclastos reduciendo el recambio óseo. Actualmente, varios trabajos de investigación asocian la osteoporosis con el inicio y la progresión de la enfermedad periodontal. Aunque la etiología de ambas es diferente, la pérdida de masa ósea comparte varias características y la terapéutica utilizada para la osteoporosis puede ser considera de valor para el tratamiento de la enfermedad periodontal. El objetivo de este estudio fue evaluar el efecto del consumo de bifosfonatos en fluido crevicular (FC) sobre los niveles de RANKL, OPG y la relación RANKL/OPG en pacientes post-menopáusicas con enfermedad periodontal y osteoporosis/ osteopenia. Se estudiaron 66 sitios periodontalmente activos obtenidos de pacientes mujeres post-menopáusicas con edades entre 45-70 años de edad con enfermedad periodontal y osteoporosis/ osteopenia. La toma del FC se realizó mediante tiras de papel de filtro estériles. Para determinar la concentración de RANKL y OPG se utilizó el ensayo de ELISA comercial siguiendo las instrucciones del fabricante. Los valores obtenidos de las citoquinas y su relación fueron comparados con el Test U de Mann-Whitney. No se observaron diferencias en las concentraciones de RANKL y OPG encontradas, ni en su relación, en pacientes con enfermedad periodontal y osteoporosis/osteopenia con y sin tratamiento de bifosfonatos. Esto sugiere que probablemente estas citoquinas no serian el blanco principal de los bifosfonatos para inhibir la resorción ósea en la enfermedad periodontal.

Topics: Diphosphonates; Female; Gingival Crevicular Fluid; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Periodontal Diseases

This cross-section study was designed to assess the effect of topical application of melatonin to the gingiva on salivary RANKL, osteoprotegrin (OPG) and melatonin levels as well as plasma melatonin in 30 patients with diabetes and periodontal disease and in a control group of 30 healthy subjects. Salivary RANKL and OPG were measured by enzyme-linked immunosorbent assay and salivary and plasma melatonin by radioimmunoassay using commercial kits. Periodontograms were performed using the Florida Probe(®). Diabetic patients were treated with topical application of melatonin (1% orabase cream formula) once daily for 20 days. Patients with diabetes showed significantly higher mean levels of salivary RANKL than healthy subjects as well as significantly lower values of salivary OPG and salivary and plasma melatonin. After treatment with melatonin, there was a statistically significant decrease of the gingival index, pocket depth and salivary levels of RANKL, and a significant rise in salivary values of OPG. Changes of salivary OPG levels before and after topical melatonin treatment correlated significantly with changes in the gingival index and pocket depth. Treatment with topical melatonin was associated with an improvement in the gingival index and pocket depth, a reduction in salivary concentrations of RANKL and increase in salivary concentrations of OPG, which indicates that melatonin has a favorable effect in slowing osteoclastogenesis, improving the quality of alveolar bone and preventing the progression of periodontal disease.

Topics: Administration, Topical; Adult; Aged; Diabetes Mellitus; Female; Gingiva; Humans; Male; Melatonin; Middle Aged; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Saliva

This study evaluated the alveolar bone response to testosterone and the impact of Resolvin D2 (RvD2) on testosterone-induced osteoblast function. For the in vivo characterization, 60 male adult rats were used. Treatments established sub-physiologic (L), normal (N), or supra-physiologic (H) concentrations of testosterone. Forty rats were subjected to orchiectomy; 20 rats received periodical testosterone injections while 20 rats received testicular sham-operation. Four weeks after the surgeries, 10 rats in each group received a subgingival ligature around the lower first molars to induce experimental periodontal inflammation and bone loss. In parallel, osteoblasts were differentiated from neonatal mice calvariae and treated with various doses of testosterone for 48 h. Cell lysates and conditioned media were used for the determination of alkaline phosphatase, osteocalcin, RANKL, and osteoprotegerin. Micro-computed tomography linear analysis demonstrated that bone loss was significantly increased for both L and H groups compared to animals with normal levels of testosterone. Gingival IL-1β expression was increased in the L group (p<0.05). Ten nM testosterone significantly decreased osteocalcin, RANKL, and OPG levels in osteoblasts; 100 nM significantly increased the RANKL:OPG ratio. RvD2 partially reversed the impact of 10 nM testosterone on osteocalcin, RANKL, and OPG. These findings suggest that both L and H testosterone levels increase inflammatory bone loss in male rats. While low testosterone predominantly increases the inflammatory response, high testosterone promotes a higher osteoblast-derived RANKL:OPG ratio. The proresolving mediator RvD2 ameliorates testosterone-derived downregulation of osteocalcin, RANKL, and OPG in primary murine osteoblasts suggesting a direct role of inflammation in osteoblast function.

Topics: Alkaline Phosphatase; Animals; Bone and Bones; Cells, Cultured; Cytokines; Docosahexaenoic Acids; Down-Regulation; Inflammation; Male; Mice; Osteoblasts; Osteocalcin; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Rats; Testosterone; X-Ray Microtomography

Osteoporosis and periodontal disease are chronic diseases, in the pathogenesis of which plasma osteoprotogerin (OPG) and RANKL are important. The study aimed to investigate the relationship between periodontal disease and plasma cytokines, vitamin D and bone mineral density in postmenopausal women with and without osteoporosis.. One hundred and eighty-five postmenopausal women with osteoporosis and 185 age- and sex-matched control subjects were recruited. Periodontal disease was subdivided into active or past periodontal disease. Osteoprotegerin, RANKL, 25-hydroxyvitamin D₃ (25OHD), biochemical markers of bone turnover (serum C-terminal telopeptide, CTX), anthropometry and bone mineral density were measured.. A significantly higher proportion of the women with osteoporosis had active or past periodontal disease or both compared with control subjects (87.6 vs. 37.8%, p < 0.001). Plasma 25OHD was significantly lower (p < 0.001) and RANKL and OPG significantly higher in the women with osteoporosis than in control subjects (p < 0.0001). RANKL, OPG and CTX were significantly higher in women with active periodontal disease than in those without (p < 0.001), as were OPG and CTX in past periodontal disease (p < 0.001). In active and past periodontal disease, 25OHD was significantly lower (p < 0.001). Multiple logistic regression analysis showed that periodontal disease was best predicted by RANKL, 25OHD, C-terminal telopeptide and weight, r² = 10.4%.. Periodontal disease is more common in women with osteoporosis and is associated with lower vitamin D and higher concentrations of RANKL and OPG. Raised cytokines may provide the underlying mechanism that links these two conditions.

Topics: Aged; Bone Density; Bone Remodeling; Calcifediol; Case-Control Studies; Collagen Type I; Cytokines; Female; Humans; Logistic Models; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides; Periodontal Diseases; RANK Ligand; Surveys and Questionnaires

Receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) are expressed in apical periodontitis, suggesting a role for these molecules during lesion development. However, the profiles of RANKL/OPG expression in periapical lesions remain unknown. In this study we investigated the patterns of RANKL and OPG mRNA expression by real-time polymerase chain reaction in human periapical granulomas (N = 44) and compared them with sites presenting characteristic bone resorbing activity: healthy (n = 14) and orthodontically stretched and compressed periodontal ligament (n = 26), healthy gingiva (n = 24), chronic gingivitis (n = 32), and chronic periodontitis (n = 34) samples. Both RANKL and OPG mRNA expression was higher in periapical granulomas when compared with healthy periodontal ligament. Distinct patterns of RANKL and OPG expression ratio were found in the granulomas and in different physiologic and pathologic conditions, with characteristic bone resorption activity potentially being indicative of the stable or progressive nature of the lesions. Lesions with radiographic image smaller than 5 mm showed higher RANKL/OPG expression than images greater than 5 mm. Periapical granulomas presented heterogeneous patterns of RANKL and OPG expression, ranging from samples with RANKL/OPG ratio similar to that seen in sites with minimal or absent bone resorption to samples with RANKL/OPG expression pattern comparable with active bone resorption sites.

Topics: Adolescent; Adult; Alveolar Bone Loss; Bone Remodeling; Dental Stress Analysis; Disease Progression; Female; Humans; Linear Models; Male; Middle Aged; Osteoprotegerin; Periapical Granuloma; Periodontal Diseases; Periodontal Ligament; Polymerase Chain Reaction; RANK Ligand; Tooth Movement Techniques

Inflammatory and immune reactions raised in response to periodontopathogens are thought to trigger periodontal tissue destruction. We therefore investigated the expression of matrix metalloproteinases (MMPs) and the osteoclastogenic factor RANKL (receptor activator of nuclear factor-kappaB ligand), their respective inhibitors TIMPs (tissue inhibitors of metalloproteinases) and OPG (osteoprotegerin) and their possible correlation with the expression of inflammatory and regulatory cytokines in the course of experimental periodontal disease in mice.. We characterized the time course of leukocyte migration and alveolar bone loss in C57BL/6 mice infected with Actinobacillus actinomycetemcomitans. Quantitative polymerase chain reaction (RealTime PCR) and ELISA were performed to determine the expression of MMPs, TIMPs, RANKL, OPG and cathepsin K, interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, interleukin-12, interleukin-4 and interleukin-10 in periodontal tissue samples harvested throughout the course of experimental disease.. Oral inoculation of A. actinomycetemcomitans results in an intense and widespread migration of leukocytes to the gingival tissues, besides marked alveolar bone resorption. Our data also demonstrate two distinct patterns of MMP/TIMP and RANKL/OPG expression in the course of experimental periodontal disease. The expression of MMPs (MMP-1, 2 and 9) and RANKL was correlated with the expression of interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma, in a time period characterized by the intense increase of inflammatory reaction and alveolar bone loss. On the other hand, interleukin-4 and interleukin-10 were associated with higher expression of TIMPs (TIMP 1, 2 and 3) and OPG, with a lower expression of MMPs and RANKL, and with reduced rates of increase of cellular infiltration in periodontal tissues and alveolar bone loss.. It is possible that the pattern of cytokines produced in periodontal tissues determines the progression and the severity of experimental periodontal disease, controlling the breakdown of soft and bone tissues through the balance between MMPs/TIMP and RANKL/OPG expression in gingival tissues.

Topics: Actinobacillus Infections; Aggregatibacter actinomycetemcomitans; Alveolar Bone Loss; Animals; Carrier Proteins; Cathepsin K; Cathepsins; Cell Movement; Cysteine Endopeptidases; Cytokines; Disease Progression; Glycoproteins; Interferon-gamma; Interleukins; Leukocytes; Ligands; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tissue Inhibitor of Metalloproteinases; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; Tumor Necrosis Factor-alpha

The authors conducted a study to determine if salivary biomarkers specific for three aspects of periodontitis--inflammation, collagen degradation and bone turnover--correlate with clinica features of periodontal disease.. The relationship between periodontal disease and the levels of interleukin-1 beta (IL-1beta), matrix metalloproteinase (MMP)-8, and osteoprotegerin (OPG) in whole saliva of 57 adults (28 "case" subjects with moderate-to-severe periodontal disease and 29 healthy control subjects) was examined in a case-control trial.. Mean levels of IL-1beta and MMP-8 in saliva were significantly higher in case subjects than in controls. Both analytes correlated with periodontal indexes, whereas, after adjustment for confounders, OPG did not. Elevated salivary levels of MMP-8 or IL-1beta (more than two standard deviations above the mean of the controls) significantly increased the risk of periodontal disease (odds ratios in the 11.3-15.4 range). Combined elevated salivary levels of MMP-8 and IL-1beta increased the risk of experiencing periodontal disease 45-fold, and elevations in all three biomarkers correlated with individual clinical parameters indicative of periodontal disease.. Salivary levels of MMP-8 and IL-1beta appear to serve as biomarkers of periodontitis.. Qualitative changes in the composition of salivary biomarkers could have significance in the diagnosis and treatment of periodontal disease.

Topics: Adult; Biomarkers; Epidemiologic Methods; Female; Gingival Crevicular Fluid; Glycoproteins; Humans; Interleukin-1; Male; Matrix Metalloproteinase 8; Middle Aged; Osteoprotegerin; Periodontal Diseases; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Saliva

Inflammatory reactions raised in response to periodontopathogens are thought to trigger pathways of periodontal tissue destruction. We therefore investigated the expression of matrix metalloproteinases (MMPs) and the osteoclastogenic factor receptor activator of nuclear factor-kappaB ligand (RANKL), their respective tissue inhibitors of metalloproteinases (TIMPs) and osteoprotegerin (OPG) in different forms of human periodontal diseases (PDs), and the possible correlation with the expression of inflammatory and regulatory cytokines.. Quantitative polymerase chain reaction (real-time PCR) was performed with gingival biopsies mRNA from aggressive (AP) and chronic periodontitis (CP) patients.. Periodontitis patients exhibit higher expression of all analyzed factors when compared with healthy tissues. The expression of MMPs and RANKL were similar in AP and CP, as well as the expression of TNF-alpha. On the other hand, the expression of TIMPs and OPG was higher in CP, and was associated with lower IFN-gamma and higher IL-10 expression, compared with AP.. It is possible that the pattern of cytokines expressed determines the stable or progressive nature of the lesions and regulates the severity of PD, driving the balance between MMPs and TIMPs, RANKL and OPG expression in the gingival tissues controlling the breakdown of soft and bone tissues and, consequently, the disease severity.

Topics: Adult; Carrier Proteins; Chronic Disease; Cytokines; Epidemiologic Methods; Gene Expression Regulation; Glycoproteins; Humans; Matrix Metalloproteinases; Membrane Glycoproteins; Osteoprotegerin; Periodontal Diseases; Polymerase Chain Reaction; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; RNA, Messenger; Tissue Inhibitor of Metalloproteinases