Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced inflammatory bone resorption, and protects against alveolar bone loss in mice

Periodontitis, an inflammatory disease of periodontal tissues, is characterized by excessive alveolar bone resorption. An increase in the receptor activator of nuclear factor-κB ligand (RANKL) to osteoprotegerin (OPG) ratio is thought to reflect the severity of periodontitis. Here, we examined alveolar bone loss in OPG-deficient (OPG−/−) mice and RANKL-overexpressing transgenic (RANKL-Tg) mice. Alveolar bone loss in OPG−/− mice at 12 weeks was significantly higher than that in RANKL-Tg mice. OPG−/− but not RANKL-Tg mice exhibited severe bone resorption especially in cortical areas of the alveolar bone. An increased number of osteoclasts was observed in the cortical areas in OPG−/− but not in RANKL-Tg mice. Immunohistochemical analyses showed many OPG-positive signals in osteocytes but not osteoblasts. OPG-positive osteocytes in the cortical area of alveolar bones and long bones were abundant in both wild-type and RANKL-Tg mice. This suggests the resorption in cortical bone areas to be prevented by OPG produced locally. To test the usefulness of OPG−/− mice as an animal model for screening drugs to prevent alveolar bone loss, we administered an antimouse RANKL antibody or risedronate, a bisphosphonate, to OPG−/− mice. They suppressed alveolar bone resorption effectively. OPG−/− mice are useful for screening therapeutic agents against alveolar bone loss.

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Inflammasomes in Alveolar Bone Loss

Frontiers in Immunology ◽

10.3389/fimmu.2021.691013 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yang Li ◽

Junqi Ling ◽

Qianzhou Jiang

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Remodeling ◽

Host Defense ◽

Alveolar Bone ◽

Bone Destruction ◽

Alveolar Bone Loss ◽

Fine Tuning ◽

Inflammasome Activation ◽

Dependent Manner

Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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Magnolol Ameliorates Ligature-Induced Periodontitis in Rats and Osteoclastogenesis:In VivoandIn VitroStudy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/634095 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 12

Author(s):

Sheng-Hua Lu ◽

Ren-Yeong Huang ◽

Tz-Chong Chou

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Periodontal Disease ◽

Alveolar Bone ◽

Morphological Changes ◽

Osteoclast Differentiation ◽

Alveolar Bone Loss ◽

Tartrate Resistant Acid Phosphatase ◽

Nuclear Factor ◽

Raw264.7 Macrophages

Periodontal disease characterized by alveolar bone resorption and bacterial pathogen-evoked inflammatory response has been believed to have an important impact on human oral health. The aim of this study was to evaluate whether magnolol, a main constituent ofMagnolia officinalis, could inhibit the pathological features in ligature-induced periodontitis in rats and osteoclastogenesis. The sterile, 3–0 (diameter; 0.2 mm) black braided silk thread, was placed around the cervix of the upper second molars bilaterally and knotted medially to induce periodontitis. The morphological changes around the ligated molars and alveolar bone were examined by micro-CT. The distances between the amelocemental junction and the alveolar crest of the upper second molars bilaterally were measured to evaluate the alveolar bone loss. Administration of magnolol (100 mg/kg, p.o.) significantly inhibited alveolar bone resorption, the number of osteoclasts on bony surface, and protein expression of receptor activator of nuclear factor-κB ligand (RANKL), a key mediator promoting osteoclast differentiation, in ligated rats. Moreover, the ligature-induced neutrophil infiltration, expression of inducible nitric oxide synthase, cyclooxygenase-2, matrix metalloproteinase (MMP)-1 and MMP-9, superoxide formation, and nuclear factor-κB activation in inflamed gingival tissues were all attenuated by magnolol. In thein vitrostudy, magnolol also inhibited the growth ofPorphyromonas gingivalis and Aggregatibacter actinomycetemcomitansthat are key pathogens initiating periodontal disease. Furthermore, magnolol dose dependently reduced RANKL-induced osteoclast differentiation from RAW264.7 macrophages, tartrate-resistant acid phosphatase (TRAP) activity of differentiated cells accompanied by a significant attenuation of resorption pit area caused by osteoclasts. Collectively, we demonstrated for the first time that magnolol significantly ameliorates the alveolar bone loss in ligature-induced experimental periodontitis by suppressing periodontopathic microorganism accumulation, NF-κB-mediated inflammatory mediator synthesis, RANKL formation, and osteoclastogenesis. These activities support that magnolol is a potential agent to treat periodontal disease.

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Structural Dissection andIn VivoEffectiveness of a Peptide Inhibitor ofPorphyromonas gingivalisAdherence toStreptococcus gordonii

Infection and Immunity ◽

10.1128/iai.00361-10 ◽

2010 ◽

Vol 79 (1) ◽

pp. 67-74 ◽

Cited By ~ 73

Author(s):

Carlo Amorin Daep ◽

Elizabeth A. Novak ◽

Richard J. Lamont ◽

Donald R. Demuth

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Alveolar Bone ◽

Alveolar Bone Loss ◽

Peptide Inhibitor ◽

Dental Biofilm ◽

Streptococcal Antigen ◽

Α Helix

ABSTRACTThe interaction of the minor fimbrial antigen (Mfa) with streptococcal antigen I/II (e.g., SspB) facilitates colonization of the dental biofilm byPorphyromonas gingivalis.We previously showed that a 27-mer peptide derived from SspB (designated BAR) resembles the nuclear receptor (NR) box protein-protein interacting domain and potently inhibits this interactionin vitro. Here, we show that the EXXP motif upstream of the NR core α-helix contributes to the Mfa-SspB interaction and that BAR reducesP. gingivaliscolonization and alveolar bone lossin vivoin a murine model of periodontitis. Substitution of Gln for Pro1171or Glu1168increased the α-helicity of BAR and reduced its inhibitory activityin vitroby 10-fold and 2-fold, respectively. To determine if BAR preventsP. gingivalisinfectionin vivo, mice were first infected withStreptococcus gordoniiand then challenged withP. gingivalisin the absence and presence of BAR. Animals that were infected with either 109CFU ofS. gordoniiDL-1 or 107CFU ofP. gingivalis33277 did not show a statistically significant increase in alveolar bone resorption over sham-infected controls. However, infection with 109CFU ofS. gordoniifollowed by 107CFU ofP. gingivalisinduced significantly greater bone loss (P< 0.01) than sham infection or infection of mice with either organism alone.S. gordonii-infected mice that were subsequently challenged with 107CFU ofP. gingivalisin the presence of BAR exhibited levels of bone resorption similar to those of sham-infected animals. Together, these results indicate that both EXXP and the NR box are important for the Mfa-SspB interaction and that BAR peptide represents a potential therapeutic that may limit colonization of the oral cavity byP. gingivalis.

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FSH Aggravates Periodontitis-related Bone Loss in Ovariectomized Rats

Journal of Dental Research ◽

10.1177/0022034509358822 ◽

2010 ◽

Vol 89 (4) ◽

pp. 366-371 ◽

Cited By ~ 34

Author(s):

S. Liu ◽

Y. Cheng ◽

M. Fan ◽

D. Chen ◽

Z. Bian

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Clinical Features ◽

Alveolar Bone ◽

Follicle Stimulating Hormone ◽

Alveolar Bone Loss ◽

Ovariectomized Rats ◽

Fsh Receptor ◽

Histochemical Tests ◽

Experimental Periodontitis

Alveolar bone loss is one of the prominent pathologic and clinical features of periodontitis. Recently, the direct effect of follicle-stimulating hormone (FSH) on bone resorption has been demonstrated. However, the effect of FSH on alveolar bone loss remains unknown. This study tested the hypothesis that FSH would exacerbate periodontitis-related alveolar bone loss. Experimental periodontitis was induced in ovariectomized rats, and the rats were treated with extrinsic FSH or its inhibitor, leuprorelin. After mandibles were collected, we performed morphological examinations to evaluate bone loss, enzyme histochemical tests for osteoclasts, and immunohistochemical examinations for FSH receptor (FSHR). The results showed that FSH significantly increased alveolar bone resorption compared with non-FSH-treated ovariectomized rats (P < 0.05), and the number of FSHR-positive cells was positively correlated with alveolar bone loss area (r = 0.682, P < 0.01). Our results suggested that FSH can aggravate alveolar bone loss by FSHR, independent of estrogen.

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Boric acid inhibits alveolar bone loss in rat experimental periodontitis through diminished bone resorption and enhanced osteoblast formation

Journal of Dental Sciences ◽

10.1016/j.jds.2019.09.009 ◽

2020 ◽

Vol 15 (4) ◽

pp. 437-444

Author(s):

Nazmus Shalehin ◽

Akihiro Hosoya ◽

Hiroaki Takebe ◽

Md Riasat Hasan ◽

Kazuharu Irie

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Boric Acid ◽

Alveolar Bone ◽

Alveolar Bone Loss ◽

Experimental Periodontitis

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Adhesion Molecule Deficiencies Increase Porphyromonas gingivalis-Induced Alveolar Bone Loss in Mice

Infection and Immunity ◽

10.1128/iai.68.6.3103-3107.2000 ◽

2000 ◽

Vol 68 (6) ◽

pp. 3103-3107 ◽

Cited By ~ 30

Author(s):

Pamela J. Baker ◽

Lisa DuFour ◽

Mark Dixon ◽

Derry C. Roopenian

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Porphyromonas Gingivalis ◽

Adhesion Molecule ◽

Alveolar Bone ◽

Oral Infection ◽

Alveolar Bone Loss ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Complete Deletion

ABSTRACT Alveolar bone resorption can be induced in specific-pathogen-free mice by oral infection with Porphyromonas gingivalis(P. J. Baker, R. T. Evans, and D. C. Roopenian, Arch. Oral Biol. 39:1035–1040, 1994). Here we used a mouse strain, C57BL/6J, which is relatively resistant to P. gingivalis-induced bone loss to examine whether partial or complete deletion of various adhesion molecules would increase susceptibility. Complete deletion of P-selectin or nearly complete lack of expression of intercellular adhesion molecule 1 (ICAM-1) led to increased susceptibility to bone resorption after oral infection, while a hypomorphic defect in β2-integrins did not. Both the total amount of bone lost and the number of sites at which there was significant loss were increased in mice deficient in either ICAM-1 or P-selectin. Each of the three adhesion molecule deficiencies was sufficient to decreaseP. gingivalis-specific serum immunoglobulin G responses, but lower antibody titers did not lead to increased bone loss in partially β2-integrin-deficient mice. In conclusion, P-selectin and ICAM-1 deficiencies increase susceptibility to and severity of alveolar bone loss after P. gingivalisinfection. This finding underscores the importance of innate immunity in protection against P. gingivalis-induced alveolar bone resorption.

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Accelerated Alveolar Bone Loss in Mice Lacking Interleukin-10

Journal of Dental Research ◽

10.1177/154405910308200812 ◽

2003 ◽

Vol 82 (8) ◽

pp. 632-635 ◽

Cited By ~ 61

Author(s):

A. Al-Rasheed ◽

H. Scheerens ◽

D.M. Rennick ◽

H.M. Fletcher ◽

D.N. Tatakis

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Inflammatory Cytokines ◽

Alveolar Bone ◽

Interleukin 10 ◽

Alveolar Bone Loss ◽

Prevotella Intermedia ◽

Pro Inflammatory Cytokines

Interleukin-10 regulates pro-inflammatory cytokines, including those implicated in alveolar bone resorption. We hypothesized that lack of interleukin-10 leads to increased alveolar bone resorption. Male interleukin-10(−/−) mice, on 129/SvEv and C57BL/6J background, were compared with age-, sex-, and strain-matched interleukin-10(+/+) controls for alveolar bone loss. Immunoblotting was used for analysis of serum reactivity against bacteria associated with colitis and periodontitis. Interleukin-10(−/−) mice had significantly greater alveolar bone loss than interleukin-10(+/+) mice (p = 0.006). The 30–40% greater alveolar bone loss in interleukin-10(−/−) mice was evident in both strains, with C57BL/6J interleukin-10(−/−) mice exhibiting the most bone loss. Immunoblotting revealed distinct interleukin-10(−/−) serum reactivity against Bacteroides vulgatus, B. fragilis, Prevotella intermedia, and, to a lesser extent, against B. forsythus. The results of the present study suggest that lack of interleukin-10 leads to accelerated alveolar bone loss.

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B-Cell RANKL Contributes to Pathogen-Induced Alveolar Bone Loss in an Experimental Periodontitis Mouse Model

Frontiers in Physiology ◽

10.3389/fphys.2021.722859 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rajendra P. Settem ◽

Kiyonobu Honma ◽

Sreedevi Chinthamani ◽

Toshihisa Kawai ◽

Ashu Sharma

Keyword(s):

B Cells ◽

Bone Resorption ◽

Bone Loss ◽

Mouse Model ◽

B Cell ◽

Alveolar Bone ◽

Alveolar Bone Loss ◽

Conditional Knockout ◽

Wild Type ◽

In The Wild

Periodontitis is a bacterially-induced inflammatory disease that leads to tooth loss. It results from the damaging effects of a dysregulated immune response, mediated largely by neutrophils, macrophages, T cells and B cells, on the tooth-supporting tissues including the alveolar bone. Specifically, infiltrating B cells at inflamed gingival sites with an ability to secrete RANKL and inflammatory cytokines are thought to play roles in alveolar bone resorption. However, the direct contribution of B cells in alveolar bone resorption has not been fully appreciated. In this study we sought to define the contribution of RANKL expressing B cells in periodontitis by employing a mouse model of pathogen-induced periodontitis that used conditional knockout mice with B cell-targeted RANKL deletion. Briefly, alveolar bone loss was assessed in the wild-type, B-cell deficient (Jh), or B-cell-RANKL deleted (RANKLΔB) mice orally infected with the periodontal pathogen Tannerella forsythia. The RANKLΔB mice were obtained by crossing Cd19-Cre knock-in mice with mice homozygous for conditional RANKL-flox allele (RANKLflox/flox). The alveolar bone resorption was determined by morphometric analysis and osteoclastic activity of the jaw bone. In addition, the bone resorptive potential of the activated effector B cells was assessed ex vivo. The data showed that the RANKL producing B cells increased significantly in the T. forsythia-infected wild-type mice compared to the sham-infected mice. Moreover, T. forsythia-infection induced higher alveolar bone loss in the wild-type and RANKLflox/flox mice compared to infection either in the B cell deficient (Jh) or the B-cell specific RANKL deletion (RANKLΔB) mice. These data established that the oral-pathogen activated B cells contribute significantly to alveolar bone resorption via RANKL production.

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