Parathyroid Hormone Protects against Periodontitis-associated Bone Loss

Parathyroid hormone (PTH) functions as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. In addition to the well-established catabolic effects (activation of bone resorption) of PTH, it is now recognized that intermittent PTH administration has anabolic effects (promotion of bone formation). The aim of this study was to investigate whether intermittent administration of PTH in rodents would block the alveolar bone loss observed in rats when a ligature model of periodontitis is used. Morphometric analysis showed that intermittent PTH administration (40 μg/kg) was able to protect the tooth site from periodontitis-induced bone resorption. In addition, there was a significant reduction in the number of inflammatory cells at the marginal gingival area in sections obtained from animals receiving PTH compared with control animals. These findings demonstrated that intermittent PTH administration was able to protect against periodontitis-associated bone loss in a rodent model.

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Telmisartan Prevents Alveolar Bone Loss by Decreasing the Expression of Osteoclasts Markers in Hypertensive Rats With Periodontal Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2020.579926 ◽

2020 ◽

Vol 11 ◽

Author(s):

Victor Gustavo Balera Brito ◽

Mariana Sousa Patrocinio ◽

Maria Carolina Linjardi de Sousa ◽

Ayná Emanuelli Alves Barreto ◽

Sabrina Cruz Tfaile Frasnelli ◽

...

Keyword(s):

Angiotensin Ii ◽

Bone Loss ◽

Bone Formation ◽

Periodontal Disease ◽

Alveolar Bone ◽

Renin Angiotensin System ◽

Alveolar Bone Loss ◽

Hypertensive Rats ◽

Bone Formation Markers ◽

Tnf Α

Periodontal disease (PD) is a prevalent inflammatory disease with the most severe consequence being the loss of the alveolar bone and teeth. We therefore aimed to evaluate the effects of telmisartan (TELM), an angiotensin II type 1 receptor (Agtr1) antagonist, on the PD-induced alveolar bone loss, in Wistar (W) and Spontaneous Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk, and 10 mg/kg TELM was concomitantly administered for 15 days. The hemimandibles were subjected to microtomography, ELISA was used for detecting tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), CXCL3, and CCL2, while qRT-PCR was used for analyzing expression of components of renin-angiotensin system (RAS) (Agt, Ace, Agt1r, Agt2r, Ace2, and Masr), and bone markers (Runx2, Osx, Catnb, Alp, Col1a1, Opn, Ocn, Bsp, Bmp2, Trap, Rank, Rankl, CtsK, Mmp-2, Mmp-9, and osteoclast-associated receptor (Oscar)). The SHR + PD group showed greater alveolar bone loss than the W + PD group, what was significantly inhibited by treatment with TELM, especially in the SHR group. Additionally, TELM reduced the production of TNF-α, IL-1β, and CXCL3 in the SHR group. The expression of Agt increased in the groups with PD, while Agtr2 reduced, and TELM reduced the expression of Agtr1 and increased the expression of Agtr2, in W and SHRs. PD did not induce major changes in the expression of bone formation markers, except for the expression of Alp, which decreased in the PD groups. The bone resorption markers expression, Mmp9, Ctsk, and Vtn, was higher in the SHR + PD group, compared to the respective control and W + PD group. However, TELM attenuated these changes and increased the expression of Runx2 and Alp. Our study suggested that TELM has a protective effect on the progression of PD, especially in hypertensive animals, as evaluated by the resorption of the lower alveolar bone. This can be partly explained by the modulation in the expression of Angiotensin II receptors (AT1R and AT2R), reduced production of inflammatory mediators, the reduced expression of resorption markers, and the increased expression of the bone formation markers.

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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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CpG immunostimulatory oligodeoxynucleotide 1826 as a novel nasal ODN adjuvant enhanced the protective efficacy of the periodontitis gene vaccine in a periodontitis model in SD rats

BMC Oral Health ◽

10.1186/s12903-021-01763-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Guohui Bai ◽

Hang Yu ◽

Xiaoyan Guan ◽

Fengjiao Zeng ◽

Xia Liu ◽

...

Keyword(s):

Bone Loss ◽

Morphometric Analysis ◽

Alveolar Bone ◽

Alveolar Bone Loss ◽

Secretory Iga ◽

Nasal Administration ◽

Cpg Odn ◽

Gene Vaccine ◽

Sd Rats ◽

Cox 2

Abstract Background We previously demonstrated that nasal administration of periodontitis gene vaccine (pVAX1-HA2-fimA) or pVAX1-HA2-fimA plus IL-15 as adjuvant provoked protective immunity in the periodontal tissue of SD rats. This study evaluated the immune effect of pVAX1-HA2-fimA plus CpG-ODN 1826 as an adjuvant in the SD rat periodontitis models to improve the efficacy of the previously used vaccine. Methods Periodontitis was induced in maxillary second molars in SD rats receiving a ligature and infected with Porphyromonas gingivalis. Forty-two SD rats were randomly assigned to six groups: A, control without P. gingivalis; B, P. gingivalis with saline; C, P. gingivalis with pVAX1; D, P. gingivalis with pVAX1-HA2-fimA; E, P. gingivalis with pVAX1-HA2-fimA/IL-15; F, P. gingivalis with pVAX1-HA2-fimA+CpG ODN 1826 (30 µg). The levels of FimA-specific and HA2-specific secretory IgA antibodies in the saliva of rats were measured by ELISA. The levels of COX-2 and RANKL were detected by immunohistochemical assay. Morphometric analysis was used to evaluate alveolar bone loss. Major organs were observed by HE staining. Results 30 μg could be the optimal immunization dose for CpG-ODN 1826 and the levels of SIgA antibody were consistently higher in the pVAX1-HA2-fimA+CpG-ODN 1826 (30 µg) group than in the other groups during weeks 1–8 (P < 0.05, except week 1 or 2). Morphometric analysis demonstrated that pVAX1-HA2-fimA+CpG-ODN 1826 (30 µg) significantly reduced alveolar bone loss in ligated maxillary molars in group F compared with groups B–E (P < 0.05). Immunohistochemical assays revealed that the levels of COX-2 and RANKL were significantly lower in group F compared with groups B–E (P < 0.05). HE staining results of the major organs indicated that pVAX1-HA2-fimA with or without CpG-ODN 1826 was not toxic for in vivo use. Conclusions These results indicated that CpG-ODN 1826 (30 µg) could be used as an effective and safe mucosal adjuvant for pVAX1-HA2-fimA in SD rats since it could elicit mucosal SIgA responses and modulate COX-2 and RANKL production during weeks 1–8, thereby inhibiting inflammation and decreasing 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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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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Alveolar bone loss in liver transplantation patients: relationship with prolonged steroid treatment and parathyroid hormone levels

Journal Of Clinical Periodontology ◽

10.1111/j.1600-051x.2007.01153.x ◽

2007 ◽

Vol 34 (12) ◽

pp. 1039-1045 ◽

Cited By ~ 9

Author(s):

Orit Oettinger-Barak ◽

Elena Segal ◽

Eli E. Machtei ◽

Shlomi Barak ◽

Yaacov Baruch ◽

...

Keyword(s):

Liver Transplantation ◽

Parathyroid Hormone ◽

Bone Loss ◽

Alveolar Bone ◽

Alveolar Bone Loss ◽

Steroid Treatment ◽

Hormone Levels

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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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Topical and intermittent application of parathyroid hormone recovers alveolar bone loss in rat experimental periodontitis

Journal of Periodontal Research ◽

10.1111/j.1600-0765.2011.01386.x ◽

2011 ◽

Vol 46 (6) ◽

pp. 655-662 ◽

Cited By ~ 22

Author(s):

K. Tokunaga ◽

H. Seto ◽

H. Ohba ◽

C. Mihara ◽

H. Hama ◽

...

Keyword(s):

Parathyroid Hormone ◽

Bone Loss ◽

Alveolar Bone ◽

Alveolar Bone Loss ◽

Experimental Periodontitis

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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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