Accelerated Alveolar Bone Loss in Mice Lacking                Interleukin-10

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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The interleukin-10 knockout mouse is highly susceptible to Porphyromonas gingivalis-induced alveolar bone loss

Journal of Periodontal Research ◽

10.1111/j.1600-0765.2004.00760.x ◽

2004 ◽

Vol 39 (6) ◽

pp. 432-441 ◽

Cited By ~ 102

Author(s):

Hajime Sasaki ◽

Yoshimasa Okamatsu ◽

Toshihisa Kawai ◽

Ralph Kent ◽

Martin Taubman ◽

...

Keyword(s):

Bone Loss ◽

Porphyromonas Gingivalis ◽

Knockout Mouse ◽

Alveolar Bone ◽

Interleukin 10 ◽

Alveolar Bone Loss

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Osteoprotegerin-Deficient Male Mice as a Model for Severe Alveolar Bone Loss: Comparison With RANKL-Overexpressing Transgenic Male Mice

Endocrinology ◽

10.1210/en.2012-1928 ◽

2013 ◽

Vol 154 (2) ◽

pp. 773-782 ◽

Cited By ~ 33

Author(s):

Masanori Koide ◽

Yasuhiro Kobayashi ◽

Tadashi Ninomiya ◽

Midori Nakamura ◽

Hisataka Yasuda ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Alveolar Bone ◽

Nuclear Factor Κb ◽

Alveolar Bone Loss ◽

Male Mice ◽

Periodontal Tissues ◽

Cortical Areas ◽

Immunohistochemical Analyses ◽

Transgenic Male

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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Lacking Interleukin-10 Regulates the Inflammasome-driven Alveolar Bone Loss

International Journal of Oral-Medical Sciences ◽

10.5466/ijoms.19.184 ◽

2020 ◽

Vol 19 (3) ◽

pp. 184-192

Author(s):

Ryoki Kobayashi ◽

Yohei Watanabe ◽

Takashi Saito ◽

Noriko M Tsuji ◽

Tetsuro Kono ◽

...

Keyword(s):

Bone Loss ◽

Alveolar Bone ◽

Interleukin 10 ◽

Alveolar Bone Loss

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

FEBS Open Bio ◽

10.1016/j.fob.2015.06.003 ◽

2015 ◽

Vol 5 (1) ◽

pp. 522-527 ◽

Cited By ~ 30

Author(s):

Tsukasa Tominari ◽

Chiho Matsumoto ◽

Kenta Watanabe ◽

Michiko Hirata ◽

Florian M.W. Grundler ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Alveolar Bone ◽

Epigallocatechin Gallate ◽

Alveolar Bone Loss

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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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IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2

International Immunology ◽

10.1093/intimm/dxz063 ◽

2019 ◽

Vol 32 (2) ◽

pp. 89-104 ◽

Cited By ~ 3

Author(s):

Asana Kamohara ◽

Hirohito Hirata ◽

Xianghe Xu ◽

Makoto Shiraki ◽

Sakuo Yamada ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bone Resorption ◽

Bone Loss ◽

Inflammatory Cytokines ◽

Immune Complexes ◽

Protein A ◽

Precursor Cells ◽

Osteoclast Precursor ◽

Deficient Mutant ◽

Pro Inflammatory Cytokines

Abstract Staphylococcus aureus is a main pathogen of osteomyelitis and protein A is a virulence factor with high affinity for IgG. In this study, we investigated whether S. aureus affects the differentiation and bone resorption of osteoclasts through the IgG-binding capacity of protein A. Staphylococcus aureus pre-treated with serum or IgG showed marked enhancement in osteoclastogenesis and bone resorption compared to non-treated S. aureus or a protein A-deficient mutant. Blocking of the Fc receptor and deletion of the Fcγ receptor gene in osteoclast precursor cells showed that enhanced osteoclastogenesis stimulated by S. aureus IgG immune complexes (ICs) was mediated by the Fc receptor on osteoclast precursor cells. In addition, osteoclastogenesis stimulated by S. aureus ICs but not the protein A-deficient mutant was markedly reduced in osteoclast precursor cells of Myd88-knockout mice. Moreover, NFATc1, Syk and NF-κB signals were necessary for osteoclastogenesis stimulated by S. aureus ICs. The results suggest the contribution of a of Toll-like receptor 2 (TLR2)-Myd88 signal to the activity of S. aureus ICs. We further examined the expression of pro-inflammatory cytokines that is known to be enhanced by FcγR-TLR cross-talk. Osteoclasts induced by S. aureus ICs showed higher expression of TNF-α and IL-1β, and marked stimulation of proton secretion of osteoclasts activated by pro-inflammatory cytokines. Finally, injection of S. aureus, but not the protein A-deficient mutant, exacerbated bone loss in implantation and intra-peritoneal administration mouse models. Our results provide a novel mechanistic aspect of bone loss induced by S. aureus in which ICs and both Fc receptors and TLR pathways are involved.

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Persistent bacterial colonization of Porphyromonas gingivalis , Prevotella intermedia , and Actinobacillus actinomycetemcomitans in periodontitis and its association with alveolar bone loss after 6 months of therapy

Journal Of Clinical Periodontology ◽

10.1034/j.1600-051x.2000.027012897.x ◽

2000 ◽

Vol 27 (12) ◽

pp. 897-903 ◽

Cited By ~ 67

Author(s):

Eros S. Chaves ◽

Marjorie K. Jeffcoat ◽

Carol C. Ryerson ◽

Brian Snyder

Keyword(s):

Bone Loss ◽

Porphyromonas Gingivalis ◽

Alveolar Bone ◽

Bacterial Colonization ◽

Alveolar Bone Loss ◽

Actinobacillus Actinomycetemcomitans ◽

Prevotella Intermedia

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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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