Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes.
Ontology highlight
ABSTRACT:
SUBMITTER: Glowacki AJ
PROVIDER: S-EPMC3831997 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 mediates various inflammatory diseases, including periodontitis; however, the underlying mechanisms of HMGB1-induced periodontal inflammation are not completely understood. Here, we examined whether anti-HMGB1 neutralizing antibody inhibits periodontal progression and investigated the molecular pathology of HMGB1 in vitro and in vivo. In vitro analysis indicated that HMGB1, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-1β (IL-1β) were secreted in response to tumor necrosis factor-α (TNF-α) stimuli in human gingival epithelial cells (HGECs) and human monocytic leukemia cells (THP-1) treated with phorbol myristate acetate. Increased levels of GM-CSF and IL-1β were observed in the conditioned media from TNF-α-stimulated HGECs and THP-1 in vitro Simultaneous stimulation with TNF-α and anti-HMGB1 antibody significantly decreased TNF-α-induced inflammatory cytokine secretion. Experimental periodontitis was induced in mice using Porphyromonas gingivalis-soaked ligatures. The extracellular translocation was confirmed in gingival epithelia in the periodontitis model mice by immunofluorescence analysis. Systemic administration of anti-HMGB1 neutralizing antibody significantly inhibited translocation of HMGB1. The anti-HMGB1 antibody inhibited periodontal inflammation, expression of IL-1β and C-X-C motif chemokine ligand 1 (CXCL1), migration of neutrophils, and bone resorption, shown by bioluminescence imaging of myeloperoxidase activity, quantitative reverse transcription-PCR (RT-PCR), and micro-computed tomography analysis. These findings indicate that HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis, and the anti-HMGB1 antibody attenuates the secretion of a series of inflammatory cytokines, consequently suppressing the progression of periodontitis.
| S-EPMC5913859 | biostudies-literature
Project description:BackgroundPeriodontitis is a bacteria-induced inflammatory disease mainly affecting periodontal tissues, leading to periodontal inflammation, bone breakdown, and loss of the tooth. The main obstacle for treating periodontitis effectively is the difficulty in finding a target that can inhibit bone loss and inflammation simultaneously. Recent studies showed that cathepsin K (CTSK) might have functions in the immune system besides its role in osteoclasts. Thus, targeting CTSK would have a potential therapeutic effect in both the bone system and the immune system during the progression of periodontitis.MethodsIn the current study, a small molecular inhibitor (odanacatib [ODN]) is explored to inhibit the function of CTSK in a bacteria-induced periodontitis mouse model.ResultsThe application of ODN decreased the number of osteoclasts, macrophages, and T cells, as well as the expression of Toll-like receptors (TLRs) in the periodontitis lesion area. Furthermore, lack of CTSK inhibited the expression of TLR4, TLR5, and TLR9 and their downstream cytokine signaling in the gingival epithelial cells in periodontitis lesions, demonstrating that the innate immune response was inhibited in periodontitis.ConclusionThe present results show that inhibition of CTSK can prevent bone loss and the immune response during the progression of periodontitis, indicating that CTSK is a promising target for treating inflammatory diseases such as periodontitis by affecting both osteoclasts and the immune system.
| S-EPMC4648620 | biostudies-literature
Project description:Bone marrow-derived cells (BMCs) are considered to be a major source of mesenchymal stem cells (MSCs) in adults and are known to be effective in periodontal tissue regeneration. However, whether endogenous BMCs are involved in periodontal tissue repair process is uncertain. We therefore created periodontal tissue defects in the buccal alveolar bone of mandibular first molars in bone marrow chimeric mice, and immunohistochemically examined the expression of stromal cell derived factor-1 (SDF-1) and the mobilization of BMCs. We found that SDF-1 expression was increased around the defects at as early as 1 week after injury and that BMCs were mobilized to the defects, while GFP+/CD45+ were rarely observed. Fluorescence-activated cell sorting (FACS) analysis demonstrated that the number of platelet-derived growth factor receptor (pdgfr) ?+/Sca-1+ (P?S) cells in the bone marrow decreased after injury. Taken together, these results suggest that BMCs are mobilized to the periodontal tissue defects. Recruitment of BMCs, including a subset of MSCs could be a new target of periodontal treatment.
| S-EPMC4207018 | biostudies-literature
Project description:Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.
| S-EPMC6544621 | biostudies-literature
Project description:B10 cells can regulate inflammatory responses in innate immunity. Toll-like receptors (TLRs) play an important role in B cell-mediated immune responses in periodontal disease. This study aimed to determine the effects of TLR-activated B10 cells on periodontal bone loss in experimental periodontitis. Spleen B cells isolated from C57BL/6J mice were cultured with Porphyromonas gingivalis lipopolysaccharide (LPS) and cytosine-phospho-guanine (CpG) oligodeoxynucleotides for 48 h. B10-enriched CD1dhi CD5+ B cells were sorted by flow cytometry and were adoptively transferred to recipient mice through tail vein injection. At the same time, P. gingivalis-soaked ligatures were placed subgingivally around the maxillary second molars and remained there for 2 weeks before the mice were euthanized. Interleukin-10 (IL-10) production and the percentage of CD1dhi CD5+ B cells were significantly increased with treatment with P. gingivalis LPS plus CpG compared to those in mice treated with P. gingivalis LPS or CpG alone. Mice with CD1dhi CD5+ B cell transfer demonstrated reduced periodontal bone loss compared to the no-transfer group and the group with CD1dlo CD5- B cell transfer. Gingival IL-10 mRNA expression was significantly increased, whereas expressions of receptor activator of NF-?B ligand (RANKL)/osteoprotegerin (OPG), tumor necrosis factor alpha (TNF-?), and IL-1? were significantly inhibited in the CD1dhi CD5+ B cell transfer group. The percentages of CD19+ IL-10+ cells, CD19+ CD1dhi CD5+ cells, and P. gingivalis-binding CD19+ cells were significantly higher in recovered mononuclear cells from gingival tissues of the CD1dhi CD5+ B cell transfer group than in tissues of the no-transfer group and the CD1dlo CD5- B cell transfer group. This study indicated that the adoptive transfer of B10 cells alleviated periodontal inflammation and bone loss in experimental periodontitis in mice.
| S-EPMC5563573 | biostudies-literature
Project description:PurposePeriodontitis is the sixth most prevalent disease worldwide and periodontal bone loss (PBL) detection is crucial for its early recognition and establishment of the correct diagnosis and prognosis. Current radiographic assessment by clinicians exhibits substantial interobserver variation. Computer-assisted radiographic assessment can calculate bone loss objectively and aid in early bone loss detection. Understanding the rate of disease progression can guide the choice of treatment and lead to early initiation of periodontal therapy.MethodologyWe propose an end-to-end system that includes a deep neural network with hourglass architecture to predict dental landmarks in single, double and triple rooted teeth using periapical radiographs. We then estimate the PBL and disease severity stage using the predicted landmarks. We also introduce a novel adaptation of MixUp data augmentation that improves the landmark localisation.ResultsWe evaluate the proposed system using cross-validation on 340 radiographs from 63 patient cases containing 463, 115 and 56 single, double and triple rooted teeth. The landmark localisation achieved Percentage Correct Keypoints (PCK) of 88.9%, 73.9% and 74.4%, respectively, and a combined PCK of 83.3% across all root morphologies, outperforming the next best architecture by 1.7%. When compared to clinicians' visual evaluations of full radiographs, the average PBL error was 10.69%, with a severity stage accuracy of 58%. This simulates current interobserver variation, implying that diverse data could improve accuracy.ConclusionsThe system showed a promising capability to localise landmarks and estimate periodontal bone loss on periapical radiographs. An agreement was found with other literature that non-CEJ (Cemento-Enamel Junction) landmarks are the hardest to localise. Honing the system's clinical pipeline will allow for its use in intervention applications.
| S-EPMC8260405 | biostudies-literature
Project description:We applied deep convolutional neural networks (CNNs) to detect periodontal bone loss (PBL) on panoramic dental radiographs. We synthesized a set of 2001 image segments from panoramic radiographs. Our reference test was the measured % of PBL. A deep feed-forward CNN was trained and validated via 10-times repeated group shuffling. Model architectures and hyperparameters were tuned using grid search. The final model was a seven-layer deep neural network, parameterized by a total number of 4,299,651 weights. For comparison, six dentists assessed the image segments for PBL. Averaged over 10 validation folds the mean (SD) classification accuracy of the CNN was 0.81 (0.02). Mean (SD) sensitivity and specificity were 0.81 (0.04), 0.81 (0.05), respectively. The mean (SD) accuracy of the dentists was 0.76 (0.06), but the CNN was not statistically significant superior compared to the examiners (p = 0.067/t-test). Mean sensitivity and specificity of the dentists was 0.92 (0.02) and 0.63 (0.14), respectively. A CNN trained on a limited amount of radiographic image segments showed at least similar discrimination ability as dentists for assessing PBL on panoramic radiographs. Dentists' diagnostic efforts when using radiographs may be reduced by applying machine-learning based technologies.
| S-EPMC6560098 | biostudies-literature
Project description:In addition to T cells' roles in immune response and autoimmune diseases, certain types of T cells, called regulatory T cells (Tregs), play important roles in microenvironment modulation for resolution and tissue regeneration. However, there are currently few options available other than introducing more Tregs or immunosuppressive drugs to locally enrich Tregs. Herein, poly(l-lactic acid) (PLLA) nanofibrous spongy microspheres (NF-SMS), PLLA/polyethylene glycol (PEG) co-functionalized mesoporous silica nanoparticles (MSN), and poly(lactic acid- co-glycolic acid) microspheres (PLGA MS) are integrated into one multibiologic delivery vehicle for in situ Treg manipulation, where the MSNs and PLGA MS were utilized to distinctly release IL-2/TGF-? and miR-10a to locally recruit T cells and stimulate their differentiation into Tregs, while PLLA NF-SMS serve as an injectable scaffold for the adhesion and proliferation of these Tregs. In a mouse model of periodontitis, the injectable and biomolecule-delivering PLLA NF-SMS lead to Treg enrichment, expansion, and Treg-mediated immune therapy against bone loss. This system can potentially be utilized in a wide variety of other immune and regenerative therapies.
| S-EPMC6205210 | biostudies-literature
Project description:ObjectiveSH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model.MethodsCIA was induced in wild-type (Sh3bp2(+/+)) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2(KI/+)) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-? production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures.ResultsSh3bp2(KI/+) mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-? and osteoclast marker genes were higher in the joints of Sh3bp2(KI/+) mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-? and IL-17 production were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) mice. In vitro experiments showed that TNF-? production in Sh3bp2(KI/+) BMMs is elevated compared with Sh3bp2(+/+) BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2(KI/+) BMMs associated with increased NFATc1 nuclear localization.ConclusionGain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.
| S-EPMC4140794 | biostudies-literature
Project description:Obesity is associated with abnormal lipid metabolism and impaired bone homeostasis. The aim of our study was to investigate the impact of specific elevated fatty acid (FA) levels on alveolar bone loss in a Porphyromonas gingivalis-induced model of periodontal disease and to analyze underlying cellular mechanisms in bone-resorbing osteoclasts and bone-forming osteoblasts in mice. Four-week-old male C57BL/6 mice were randomly divided in groups and subjected to a palmitic acid (PA)- or oleic acid (OA)-enriched high-fat diet (HFD) (20% of calories from FA) or a normal caloric diet (C group) (10% of calories from FA) for 16 wk. Starting at week 10, mice were infected orally with P. gingivalis (W50) or placebo to induce alveolar bone loss. Animals were sacrificed, and percentage fat, serum inflammation (tumor necrosis factor [TNF]-α), and bone metabolism (osteocalcin [OC], carboxy-terminal collagen crosslinks [CTX], and N-terminal propeptides of type I procollagen [P1NP]) markers were measured. Osteoblasts and osteoclasts were cultured in the presence of elevated PA or OA levels and exposed to P. gingivalis. Animals on FA-enriched diets weighed significantly more compared with animals on a normal caloric diet (P < 0.05). Both obese groups had similar percentages of fat (P = nonsignificant); however, alveolar bone loss was significantly greater in animals that were on the PA-enriched HFD (P < 0.05). TNF-α levels were highest in the PA group (P < 0.001) and increased in all groups in response to P. gingivalis inoculation (P < 0.01), whereas bone remodeling markers OC, CTX, and P1NP were lowest in the PA group (P < 0.001) and highest in the C group. Bacterial challenge decreased bone metabolism markers in all groups (P < 0.01). Further, osteoclasts showed an augmented inflammatory response to P. gingivalis in the presence of hyperlipidemic PA levels as opposed to OA cultures, which responded similarly to controls. These findings indicate that the specific FA profile of diet rather than weight gain and obesity alone modulates bone metabolism and can therefore influence alveolar bone loss.
| S-EPMC4720954 | biostudies-literature