Simvastatin inhibits LPS-induced alveolar bone loss during metabolic syndrome.
Ontology highlight
ABSTRACT:
SUBMITTER: Jin J
PROVIDER: S-EPMC3929976 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Local delivery of simvastatin (SIM) has exhibited potential in preventing inflammation and limiting bone loss associated with experimental periodontitis. The primary aim of this study was to analyze transcriptome changes that may contribute to SIM's reduction of periodontal inflammation and bone loss. We evaluate the global genetic profile and signaling mechanisms induced by SIM on experimental periodontitis bone loss and inflammation. Twenty mature female Sprague Dawley rats were subjected to ligature-induced experimental periodontitis around maxillary second molars (M2) either unilaterally (one side untreated, n = 10) or bilaterally (n = 10). After the ligature removal at day 7, sites were injected with either carrier, pyrophosphate (PPi ×3), 1.5-mg SIM-dose equivalent SIM-pyrophosphate prodrug, or no injection. Three days after ligature removal, animals were euthanized; the M1-M2 interproximal was evaluated with μCT, histology, and protein expression. M2 palatal gingiva was harvested for RNA sequencing. Although ligature alone caused upregulation of proinflammatory and bone catabolic genes and proteins, seen in human periodontitis, SIM-PPi upregulated anti-inflammatory (IL-10, IL-1 receptor-like 1) and bone anabolic (insulin-like growth factor, osteocrin, fibroblast growth factor, and Wnt/ β-catenin) genes. The PPi carrier alone did not have these effects. Genetic profile and signaling mechanism data may help identify enhanced pharmacotherapeutic approaches to limit or regenerate periodontitis bone loss. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
| S-EPMC6524672 | biostudies-literature
Project description:(-)-Epigallocatechin-3-O-gallate (EGCG), present in green tea, exhibits antioxidant and antiallergy effects. EGCG3″Me, a 3-O-methylated derivative of EGCG, has been reported to show similar biological functions; the inhibitory activity of EGCG3″Me in a mouse allergy model was more potent than that of EGCG, probably due to the efficiency of absorption from the intestine. However, the functional potency of these EGCGs is controversial in each disease model. We previously observed that EGCG suppressed inflammatory bone resorption and prevented alveolar bone loss in a mouse model of periodontosis. In this study, we examined the role of EGCG3″Me in bone resorption using a mouse model of periodontitis. Lipopolysaccharide (LPS)-induced osteoclast formation was suppressed by adding EGCG3″Me to cocultures of osteoblasts and bone marrow cells, and LPS-induced bone resorption was also inhibited by EGCG3″Me in calvarial organ cultures. EGCG3″Me acted on osteoblasts and suppressed prostaglandin E (PGE) production, which is critical for inflammatory bone resorption, by inhibiting the expression of COX-2 and mPGES-1, key enzymes for PGE synthesis. In osteoclast precursor macrophages, EGCG3″Me suppressed RANKL-dependent differentiation into mature osteoclasts. In a mouse model of periodontitis, LPS-induced bone resorption was suppressed by EGCG3″Me in organ culture of mouse alveolar bone, and the alveolar bone loss was further attenuated by the treatment of EGCG3″Me in the lower gingiva in vivo. EGCG3″Me may be a potential natural compound for the protection of inflammatory bone loss in periodontitis.
| S-EPMC5715342 | biostudies-other
Project description:Periodontitis-mediated alveolar bone loss is caused by dysbiotic shifts in the commensal oral microbiota that upregulate proinflammatory osteoimmune responses. The study purpose was to determine whether antimicrobial-induced disruption of the commensal microbiota has deleterious effects on alveolar bone. We administered an antibiotic cocktail, minocycline, or vehicle-control to sex-matched C57BL/6T mice from age 6- to 12 weeks. Antibiotic cocktail and minocycline had catabolic effects on alveolar bone in specific-pathogen-free (SPF) mice. We then administered minocycline or vehicle-control to male mice reared under SPF and germ-free conditions, and we subjected minocycline-treated SPF mice to chlorhexidine oral antiseptic rinses. Alveolar bone loss was greater in vehicle-treated SPF versus germ-free mice, demonstrating that the commensal microbiota drives naturally occurring alveolar bone loss. Minocycline- versus vehicle-treated germ-free mice had similar alveolar bone loss outcomes, implying that antimicrobial-driven alveolar bone loss is microbiota dependent. Minocycline induced phylum-level shifts in the oral bacteriome and exacerbated naturally occurring alveolar bone loss in SPF mice. Chlorhexidine further disrupted the oral bacteriome and worsened alveolar bone loss in minocycline-treated SPF mice, validating that antimicrobial-induced oral dysbiosis has deleterious effects on alveolar bone. Minocycline enhanced osteoclast size and interface with alveolar bone in SPF mice. Neutrophils and plasmacytoid dendritic cells were upregulated in cervical lymph nodes of minocycline-treated SPF mice. Paralleling the upregulated proinflammatory innate immune cells, minocycline therapy increased TH 1 and TH 17 cells that have known pro-osteoclastic actions in the alveolar bone. This report reveals that antimicrobial perturbation of the commensal microbiota induces a proinflammatory oral dysbiotic state that exacerbates naturally occurring alveolar bone loss.
| S-EPMC8732259 | biostudies-literature
Project description:Clinical studies have shown that metabolic syndrome (MetS) is associated with increased risk of developing periodontitis. However, the underlying mechanisms remain largely unknown. Since it is known that lipopolysaccharide (LPS)-activated toll-like receptor 4 signaling pathways play a crucial role in periodontitis, we hypothesized that MetS enhances LPS-induced periodontal inflammation and alveolar bone loss. In this study, we induced MetS in C57BL/6 mice by feeding them high-fat diet (HFD), and we induced periodontitis by periodontal injection of Aggregatibacter actinomycetemcomitans LPS. We found that mice fed a HFD had significantly increased body weight, plasma lipids, insulin, and insulin resistance when compared with mice fed regular chow, indicating that the mice developed MetS. We also found that a HFD markedly increased LPS-induced alveolar bone loss, osteoclastogenesis, and inflammatory infiltration. Analysis of gene expression in periodontal tissue revealed that HFD and LPS injection cooperatively stimulated expression of cytokines that are known to be involved in periodontal tissue inflammation and osteoclastogenesis-such as interleukin 6, monocyte-chemotactic protein 1, receptor activator of nuclear factor kappa-B ligand, and macrophage colony-stimulating factor. To further understand the potential mechanisms involved in MetS-boosted tissue inflammation, our in vitro studies showed that palmitic acid-the most abundant saturated fatty acid (SFA) and the major SFA in the HFD used in our animal study-potently enhanced LPS-induced proinflammatory gene expression in macrophages. In sum, this study demonstrated that MetS was associated with increased periodontal inflammation and alveolar bone loss in an LPS-induced periodontitis animal model. This study also suggests that SFA palmitic acid may play an important role in MetS-associated periodontitis by enhancing LPS-induced expression of inflammatory cytokines in macrophages.
| S-EPMC4300302 | biostudies-other
Project description:Osteoporosis and osteoporotic fractures comprise a substantial health and socioeconomic burden. The leading cause of osteoporosis is an imbalance in bone formation and bone resorption caused by hyperactive osteoclasts. Therefore, a new strategy to suppress osteoclastogenesis is needed. Parkin is likely closely associated with bone metabolism, although its role in osteoclastogenesis is unclear. In this study, the Parkin protein inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation, osteoclast-specific gene expression, F-actin ring formation, and bone resorption pit formation in vitro. Moreover, depletion of Parkin enhanced RANKL-induced osteoclast formation, osteoclast-specific gene expression, F-actin ring formation, and bone resorption pit formation. Reactive oxygen species (ROS) activity was suppressed, while autophagy was upregulated with the presence of the Parkin protein. ROS activity was upregulated and autophagy was decreased due to Parkin knockdown. In addition, intravenous administration of Parkin rescued ovariectomy-induced bone loss and reduced osteoclastogenesis in vivo. Collectively, Parkin has therapeutic potential for diseases associated with overactive osteoclasts.
| S-EPMC9687699 | biostudies-literature
Project description:Osteoimmunology focuses on the intermodulation between bone and the immune system. Lipopolysaccharide (LPS)-induced bone loss models are commonly used to investigate the interface between inflammation and osteoporosis. Circulating exosomes can regulate physiological and pathological processes through exosomal microRNAs and proteins. In this study, we observed reduced osteoblast number and bone formation in LPS-induced bone loss mice (LPS mice). Levels of circulating exosomes were increased by ~ twofold in LPS mice, and the expression of exosomal miRNAs was significantly changed. miRNAs (miRNA-125b-5p, miRNA-132-3p, and miRNA-214-3p) that were reported to inhibit osteoblast activity were significantly increased in the serum exosomes and bone tissues of LPS mice. Additionally, LPS-induced increases in exosomes significantly inhibited the osteogenic differentiation of MC3T3-E1 cells.
| S-EPMC9300544 | biostudies-literature
Project description:Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Although its pathogenesis remains unclear, a number of studies indicate that microglia-mediated neuroinflammation makes a great contribution to the pathogenesis of PD. Melatonin receptor 1 (MT1) is widely expressed in glia cells and neurons in substantia nigra (SN). Neuronal MT1 is a neuroprotective factor, but it remains largely unknown whether dysfunction of microglial MT1 is involved in the PD pathogenesis. Here, we found that MT1 was reduced in microglia of SN in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Microglial MT1 activation dramatically inhibited lipopolysaccharide (LPS)-induced neuroinflammation, whereas loss of microglial MT1 aggravated it. Metabolic reprogramming of microglia was found to contribute to the anti-inflammatory effects of MT1 activation. LPS-induced excessive aerobic glycolysis and impaired oxidative phosphorylation (OXPHOS) could be reversed by microglial MT1 activation. MT1 positively regulated pyruvate dehydrogenase alpha 1 (PDHA1) expression to enhance OXPHOS and suppress aerobic glycolysis. Furthermore, in LPS-treated microglia, MT1 activation decreased the toxicity of conditioned media to the dopaminergic (DA) cell line MES23.5. Most importantly, the anti-inflammatory effects of MT1 activation were observed in LPS-stimulated mouse model. In general, our study demonstrates that MT1 activation inhibits LPS-induced microglial activation through regulating its metabolic reprogramming, which provides a mechanistic insight for microglial MT1 in anti-inflammation.
| S-EPMC8208780 | biostudies-literature
Project description:The lymphatic system plays a crucial role in the maintenance of tissue fluid homeostasis and the immunological response to inflammation. The effects of lymphatic drainage dysfunction on periodontitis have not been well studied. Here we show that lymphatic vessel endothelial receptor 1 (LYVE1)+ /podoplanin (PDPN)+ lymphatic vessels (LVs) are increased in the periodontal tissues, with accumulation close to the alveolar bone surface, in two murine periodontitis models: rheumatoid arthritis (RA)-associated periodontitis and ligature-induced periodontitis. Further, PDPN+ /alpha-smooth muscle actin (αSMA)- lymphatic capillaries are increased, whereas PDPN+ /αSMA+ collecting LVs are decreased significantly in the inflamed periodontal tissues. Both mouse models of periodontitis have delayed lymph flow in periodontal tissues, increased TRAP-positive osteoclasts, and significant alveolar bone loss. Importantly, the local administration of adeno-associated virus for vascular endothelial growth factor C, the major growth factor that promotes lymphangiogenesis, increases the area and number of PDPN+ /αSMA+ collecting LVs, promotes local lymphatic drainage, and reduces alveolar bone loss in both models of periodontitis. Lastly, LYVE1+ /αSMA- lymphatic capillaries are increased, whereas LYVE1+ /αSMA+ collecting LVs are decreased significantly in gingival tissues of patients with chronic periodontitis compared with those of clinically healthy controls. Thus, our findings reveal an important role of local lymphatic drainage in periodontal inflammation-mediated alveolar bone loss. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| S-EPMC10587832 | biostudies-literature
Project description:Adipose tissue fibrosis with chronic inflammation is a hallmark of obesity-related metabolic disorders, and the role of proteoglycans in developing adipose tissue fibrosis is of interest. Periodontal disease is associated with obesity; however, the underlying molecular mechanisms remain unclear. Here we investigated the roles of periodontal ligament associated protein-1 (PLAP-1)/asporin, a proteoglycan preferentially and highly expressed in the periodontal ligament, in obesity-related adipose tissue dysfunction and adipocyte differentiation. It was found that PLAP-1 is also highly expressed in white adipose tissues. Plap-1 knock-out mice counteracted obesity and alveolar bone resorption induced by a high-fat diet. Plap-1 knock-down in 3T3-L1 cells resulted in less lipid accumulation, and recombinant PLAP-1 enhanced lipid accumulation in 3T3-L1 cells. In addition, it was found that primary preadipocytes isolated from Plap-1 knock-out mice showed lesser lipid accumulation than the wild-type (WT) mice. Furthermore, the stromal vascular fraction of Plap-1 knock-out mice showed different extracellular matrix gene expression patterns compared to WT. These findings demonstrate that PLAP-1 enhances adipogenesis and could be a key molecule in understanding the association between periodontal disease and obesity-related metabolic disorders.
| S-EPMC7925592 | biostudies-literature
Project description:ObjectivesNLRP3 inflammasome is a critical part of the innate immune system and plays an important role in a variety of inflammatory diseases. However, the effects of NLRP3 inflammasome on periodontitis have not been fully studied.Materials and methodsWe used ligature-induced periodontitis models of NLRP3 knockout mice (NLRP3KO ) and their wildtype (WT) littermates to compare their alveolar bone phenotypes. We further used Lysm-Cre/RosanTnG mouse to trace the changes of Lysm-Cre+ osteoclast precursors in ligature-induced periodontitis with or without MCC950 treatment. At last, we explored MCC950 as a potential drug for the treatment of periodontitis in vivo and in vitro.ResultsHere, we showed that the number of osteoclast precursors, osteoclast differentiation and alveolar bone loss were reduced in NLRP3KO mice compared with WT littermates, by using ligature-induced periodontitis model. Next, MCC950, a specific inhibitor of the NLRP3 inflammasome, was used to inhibit osteoclast precursors differentiation into osteoclast. Further, we used Lysm-Cre/RosanTnG mice to demonstrate that MCC950 decreases the number of Lysm-Cre+ osteoclast precursors in ligature-induced periodontitis. At last, treatment with MCC950 significantly suppressed alveolar bone loss with reduced IL-1β activation and osteoclast differentiation in ligature-induced periodontitis.ConclusionOur findings reveal that NLRP3 regulates alveolar bone loss in ligature-induced periodontitis by promoting osteoclastic differentiation.
| S-EPMC7849172 | biostudies-literature