Osteoclastogenesis in periodontal diseases: Possible mediators and mechanisms

AlQranei, Mohammed S.; Chellaiah, Meenakshi A.

doi:10.1016/j.job.2020.02.002

Cited by 53 publications

(44 citation statements)

References 84 publications

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“…TLR4 is a surface receptor that activates the innate immune response. This TLR receptor can mediate bacterial LPS signaling [ 51 ]. Data on whether LPS binds TLR4, TLR2, or both remain inconclusive.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling

et al. 2021

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Background Lipopolysaccharide (LPS) is an endotoxin and a vital component of gram-negative bacteria’s outer membrane. During gram-negative bacterial sepsis, LPS regulates osteoclast differentiation and activity, in addition to increasing inflammation. This study aimed to investigate how LPS regulates osteoclast differentiation of RAW 264.7 cells in vitro. Results Herein, we revealed that RAW cells failed to differentiate into mature osteoclasts in vitro in the presence of LPS. However, differentiation occurred in cells primed with receptor activator of nuclear factor-kappa-Β ligand (RANKL) for 24 h and then treated with LPS for 48 h (henceforth, denoted as LPS-treated cells). In cells treated with either RANKL or LPS, an increase in membrane levels of toll-like receptor 4 (TLR4) receptor was observed. Mechanistically, an inhibitor of TLR4 (TAK-242) reduced the number of osteoclasts as well as the secretion of tumor necrosis factor (TNF)-α in LPS-treated cells. RANKL-induced RAW cells secreted a very basal level TNF-α. TAK-242 did not affect RANKL-induced osteoclastogenesis. Increased osteoclast differentiation in LPS-treated osteoclasts was not associated with the RANKL/RANK/OPG axis but connected with the LPS/TLR4/TNF-α tumor necrosis factor receptor (TNFR)-2 axis. We postulate that this is because TAK-242 and a TNF-α antibody suppress osteoclast differentiation. Furthermore, an antibody against TNF-α reduced membrane levels of TNFR-2. Secreted TNF-α appears to function as an autocrine/ paracrine factor in the induction of osteoclastogenesis independent of RANKL. Conclusion TNF-α secreted via LPS/TLR4 signaling regulates osteoclastogenesis in macrophages primed with RANKL and then treated with LPS. Our findings suggest that TLR4/TNF-α might be a potential target to suppress bone loss associated with inflammatory bone diseases, including periodontitis, rheumatoid arthritis, and osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling

et al. 2021

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“…Activated inflammatory cascade elevates the level of pro-inflammatory cytokines in periodontal tissue, including IL-6, IL-1β, and TNF-α. Elevated levels of pro-inflammatory cytokines in alveolar bone induce osteoclastogenesis and osteoclastogenic bone resorption ( Pan et al, 2019 ; AlQranei and Chellaiah, 2020 ; Xu et al, 2020 ). Activation of MAPK (p38) signaling in various immune cells regulates periodontal disease progression and alveolar bone loss ( Li et al, 2012 ; Xu et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

SLIT2 Overexpression in Periodontitis Intensifies Inflammation and Alveolar Bone Loss, Possibly via the Activation of MAPK Pathway

Wang

Zheng

Pathak

et al. 2020

Front. Cell Dev. Biol.

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SLIT2, a member of neuronal guidance cues, has been reported to regulate inflammation and cancer progression. Periodontitis is an oral inflammatory disease that degenerates periodontal tissue, alveolar bone and tooth. This study aims to explore the expression pattern of SLIT2 in periodontitis and its role in disease progression and bone loss. Gingival tissue of 20 periodontitis patients and 20 healthy-controls was obtained. Ligature-induced periodontitis (LIP) mice-model was developed in Slit2-Tg and wild-type mice. The effect of SLIT2 on inflammation, immune cell infiltration, M1 macrophage polarization, and alveolar bone loss in periodontitis was analyzed extensively. In periodontitis-affected gingival-tissue, SLIT2 expression was 4.4-fold higher compared to healthy-volunteers. LIP enhanced SLIT2 expression in mice periodontitis-affected periodontal tissue (PAPT) and blood circulation of wild-type mice by 4. 6-, and 5.0-fold, respectively. In Slit2-Tg-mice PAPT, SLIT2 expression was 1.8-fold higher compared to wild-type mice. Micro-CT and histomorphometric analysis revealed a 1.3-fold higher cement-enamel-junction to the alveolar-bone-crest (CEJ-ABC) distance and alveolar bone loss in LIP Slit2-Tg-mice compare to LIP wild-type mice. Results from RNA-sequencing, RT-qPCR, and ELISA showed a higher expression of Cxcr2, Il-18, TNFα, IL-6, and IL-1β in Slit2-Tg-mice PAPT compared to wild-type-mice. Slit2-Tg-mice PAPT showed a higher number of osteoclasts, M1 macrophages, and the upregulation of Robo1 expression. Slit2-Tg-mice PAPT showed upregulation of M1 macrophage marker CD16/32 and osteoclastogenic markers Acp5 , Ctsk , and Nfatc1 , but osteogenic markers ( Alp, Bglap ) remained unchanged. Immunohistochemistry unveiled the higher vasculature and infiltration of leucocytes and macrophages in Slit2-Tg-mice PAPT. RNA-sequencing, GO-pathway enrichment analysis, and western blot analysis revealed the activation of the MAPK signaling pathway in Slit2 -Tg mice PAPT. In conclusion, SLIT2 overexpression in periodontitis intensifies inflammation, immune cells infiltration, M1 macrophage polarization, osteoclastogenesis, and alveolar bone loss, possibly via activation of MAPK signaling, suggesting the role of SLIT2 on exacerbation of periodontitis and alveolar bone loss.

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“…Under normal circumstances the pathogenic organisms would be removed, the recruited leucocytes would undergo apoptosis and tissue destruction would be reversible, thus constituting gingivitis. However, under certain conditions that are not fully understood, the pathogenic bacteria continue to replicate and cannot be controlled by the acute immune response, which then becomes chronic and unresolved, resulting in progressive fibrosis and in the irreversible destruction of soft tissue and local bone, thus constituting periodontal disease [ 39 , 40 ].…”

Section: Pathophysiology Of Periodontal Diseasementioning

confidence: 99%

Tobacco Use and Periodontal Disease—The Role of Microvascular Dysfunction

Silva

2021

Biology

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Periodontal disease consists in highly prevalent wide-ranging inflammatory conditions that affect the supporting apparatus of teeth. Tobacco use is the most important risk factor for periodontal disease as it increases disease severity and periodontal surgery complications. Tobacco use is harmful for the vasculature by causing microvascular dysfunction, which is known to negatively affect periodontal disease. To the author’s knowledge this paper is the first comprehensive review on the mechanisms by which tobacco use affects oral microcirculation and impacts the pathophysiology of periodontal disease. In healthy subjects, acute nicotine administration or tobacco use (smoking/smokeless forms) increases the blood flow in the oral mucosa due to local irritation and increased blood pressure, which overcome neural- and endocrine-mediated vasoconstriction. Chronic tobacco smokers display an increased gingival microvascular density, which is attributed to an increased capillary recruitment, however, these microcirculatory units show higher tortuosity and lower caliber. These morphological changes, together with the repetitive vasoconstrictive insults, contribute to lower gingival perfusion in chronic smokers and do not completely regress upon smoking cessation. In periodontal disease there is considerable gingival inflammation and angiogenesis in non-smokers which, in chronic smokers, are considerably suppressed, in part due to local immune suppression and oxidative stress. Tobacco exposure, irrespective of the form of use, causes long-term microvascular dysfunction that increases the risk of complications due to the natural disease course or secondary therapeutic strategies.

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Osteoclastogenesis in periodontal diseases: Possible mediators and mechanisms

Cited by 53 publications

References 84 publications

Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling

Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling

SLIT2 Overexpression in Periodontitis Intensifies Inflammation and Alveolar Bone Loss, Possibly via the Activation of MAPK Pathway

Tobacco Use and Periodontal Disease—The Role of Microvascular Dysfunction

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