The serum immunoglobulin G titres against Porphyromonas gingivalis as a predictor of clinical response to 1-year treatment with biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients: A retrospective cohort study.

OBJECTIVES: The aim is to evaluate the relevance of serum immunoglobulin G (IgG) titres against periodontopathic bacteria to predict the clinical response to 1-year treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) patients. METHODS: Data were collected from 50 RA patients who had received conventional synthetic DMARDs, corticosteroids, or non-steroidal anti-inflammatory drugs before (baseline) and after 1-year treatment with bDMARDs in a retrospective cohort study. Changes in rheumatologic conditions were compared between the two groups for low and high baseline IgG titres against Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans according to their median measurements. RESULTS: Twenty-five patients with low anti-P. gingivalis IgG titres showed significantly greater decreases in changes in the Clinical Disease Activity Index and swollen joint count than 25 patients with high anti-P. gingivalis IgG titres (p = .04 for both). Bivariate and multivariate analyses revealed a significantly positive association of baseline anti-P. gingivalis IgG titres with Clinical Disease Activity Index changes (p = .02 and p = .002). However, post-treatment rheumatologic conditions were comparable between 25 patients each in the low and high baseline anti-A. actinomycetemcomitans IgG titre groups. CONCLUSIONS: Baseline serum anti-P. gingivalis IgG titres are predictive of the clinical response to 1-year treatment with bDMARDs in RA patients.

Periodontitis severity affects the clinical response to biological disease-modifying antirheumatic drugs in rheumatoid arthritis: A 1-year follow-up study.

OBJECTIVES: To assess whether periodontitis severity affects the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) for 1 year in rheumatoid arthritis (RA) patients. METHODS: Data were collected from 50 RA patients who had received corticosteroids, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 1 year of bDMARD therapy in a retrospective study. Rheumatologic conditions were compared between the two periodontitis severity groups according to the periodontal inflamed surface area (PISA) or Centers for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) case definitions. RESULTS: Twenty-eight patients with no or mild periodontitis showed significantly greater decreases in changes in Clinical Disease Activity Index (CDAI) and tender and swollen joint count in comparison to 22 patients with moderate and severe periodontitis (p = .02, p = .01, and p = .03). Both bivariate and multivariate analyses revealed a significantly positive association between the baseline CDC/AAP definitions and CDAI changes (p = .005 and p = .0038). However, rheumatologic conditions were comparable between 25 patients each in the low and high PISA groups. CONCLUSIONS: Baseline periodontitis severity according to the CDC/AAP definitions is associated with the clinical response to bDMARDs for 1 year in RA patients.

Osteoimmunology in Periodontitis: Local Proteins and Compounds to Alleviate Periodontitis.

Periodontitis is one of the most common oral diseases resulting in gingival inflammation and tooth loss. Growing evidence indicates that it results from dysbiosis of the oral microbiome, which interferes with the host immune system, leading to bone destruction. Immune cells activate periodontal ligament cells to express the receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) and promote osteoclast activity. Osteocytes have active roles in periodontitis progression in the bone matrix. Local proteins are involved in bone regeneration through functional immunological plasticity. Here, we discuss the current knowledge of cellular and molecular mechanisms in periodontitis, the roles of local proteins, and promising synthetic compounds generating a periodontal regeneration effect. It is anticipated that this may lead to a better perception of periodontitis pathophysiology.

Association among periodontitis severity, anti-agalactosyl immunoglobulin G titer, and the disease activity of rheumatoid arthritis.

OBJECTIVE: The aim of the present study was to evaluate the association between the periodontal and serological parameters and the disease activity of rheumatoid arthritis (RA) and between the anti-agalactosyl immunoglobulin G (IgG) titer and periodontitis severity. The objective was also to assess the effect of supragingival scaling on the serological parameters in patients with RA. BACKGROUND: The periodontal and serological parameters in relation to the autoimmune inflammatory response have been linked to RA disease activity. However, the association of the anti-agalactosyl IgG titer with RA disease activity and periodontitis severity has not been elucidated. METHODS: The periodontal, rheumatologic, and serological data were collected from 127 patients with RA in a retrospective cohort study. Of the 127 patients, 21 had been randomly assigned to receive oral hygiene instruction and supragingival scaling. The anti-agalactosyl IgG titer was determined by an electrochemiluminescence immunoassay. RESULTS: The patients with a moderate to high RA disease activity showed significantly higher levels of probing depth (PD), clinical attachment level, anti-cyclic citrullinated peptide IgG, and anti-agalactosyl IgG titer and greater mean percentages of severe periodontitis than those with a low RA disease activity (p < .05 for all). Both univariate and multivariate analyses revealed a significantly positive correlation between the PD and RA disease activity (p = .009 and p = .001), between the anti-agalactosyl IgG titer and RA disease activity (p = .002 and p < .001), and between the anti-agalactosyl IgG titer and PD (p < .001 for both). Supragingival scaling significantly decreased the anti-agalactosyl IgG titer (p = 0.03). CONCLUSION: The PD and anti-agalactosyl IgG titer are positively interrelated, both of which are correlated positively with RA disease activity and influenced by supragingival scaling in patients with RA.

Ingestion of Porphyromonas gingivalis exacerbates colitis via intestinal epithelial barrier disruption in mice.

OBJECTIVE: This study aimed to evaluate the effects of ingested periodontal pathogens on experimental colitis in mice and to elucidate its underlying mechanisms. BACKGROUND: Inflammatory bowel disease (IBD) is defined as a chronic intestinal inflammation that results in damage to the gastrointestinal tract. Epidemiological studies have shown an association between IBD and periodontitis. Although a large number of ingested oral bacteria reach gastrointestinal tract constantly, the effect of ingested periodontal pathogens on intestinal inflammation is still unknown. METHODS: Experimental colitis was induced by inclusion of dextran sodium sulfate solution in drinking water of the mice. Major periodontal pathogens (Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum) were administered orally every day during the experiment. The severity of colitis between the groups was compared. In vitro studies of the intestinal epithelial cell line were conducted to explore the molecular mechanisms by which periodontal pathogens affect the development of colitis. RESULTS: The oral administration of P. gingivalis significantly increased the severity of colitis when compared to other pathogens in the DSS-induced colitis model. The ingested P. gingivalis disrupted the colonic epithelial barrier by decreasing the expression of tight junction proteins in vivo. In vitro permeability assays using the intestinal epithelial cell line suggested the P. gingivalis-specific epithelial barrier disruption. The possible involvement of gingipains in the exacerbation of colitis was implied by using P. gingivalis lacking gingipains. CONCLUSION: Porphyromonas gingivalis exacerbates gastrointestinal inflammation by directly interacting with the intestinal epithelial barrier in a susceptible host.

The periodontal inflamed surface area is associated with the clinical response to biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a retrospective study.

Objectives: We evaluated whether the periodontal inflamed surface area (PISA), a measure of the inflammatory burden posed by periodontitis, is associated with the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA).Methods: We conducted a retrospective study that collected rheumatologic and periodontal data from 54 patients with RA who had received corticosteroid, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 6 months of bDMARD therapy. After the patients were divided into two groups based on high or low PISA according to the median measurements at baseline, the rheumatologic condition was compared between the groups.Results: The patients with a low PISA showed significantly lower values for the Clinical Disease Activity Index (CDAI) (p = .008), swollen joint count (p = .02), and patient's and evaluator's global assessment (p = .01 and p = .03) and significantly greater decreases in changes in the CDAI from baseline to 6 months than the patients with a high PISA (p = .01), although these values were comparable at baseline. Both univariate and multivariate analyses revealed a significantly positive correlation between the baseline PISA and changes in the CDAI (p = .04 and p < .001).Conclusion: The PISA is associated with the clinical response to bDMARDs in patients with RA.

Aggregatibacter actinomycetemcomitans induces detachment and death of human gingival epithelial cells and fibroblasts via elastase release following leukotoxin-dependent neutrophil lysis.

Aggregatibacter actinomycetemcomitans is considered to be associated with periodontitis. Leukotoxin (LtxA), which destroys leukocytes in humans, is one of this bacterium's major virulence factors. Amounts of neutrophil elastase (NE), which is normally localized in the cytoplasm of neutrophils, are reportedly increased in the saliva of patients with periodontitis. However, the mechanism by which NE is released from human neutrophils and the role of NE in periodontitis is unclear. In the present study, it was hypothesized that LtxA induces NE release from human neutrophils, which subsequently causes the breakdown of periodontal tissues. LtxA-treatment did not induce significant cytotoxicity against human gingival epithelial cells (HGECs) or human gingival fibroblasts (HGFs). However, it did induce significant cytotoxicity against human neutrophils, leading to NE release. Furthermore, NE and the supernatant from LtxA-treated human neutrophils induced detachment and death of HGECs and HGFs, these effects being inhibited by administration of an NE inhibitor, sivelestat. The present results suggest that LtxA mediates human neutrophil lysis and induces the subsequent release of NE, which eventually results in detachment and death of HGECs and HGFs. Thus, LtxA-induced release of NE could cause breakdown of periodontal tissue and thereby exacerbate periodontitis.

Pneumococcal DNA-binding proteins released through autolysis induce the production of proinflammatory cytokines via toll-like receptor 4.

Streptococcus pneumoniae is a leading cause of bacterial pneumonia. Our previous study suggested that S. pneumoniae autolysis-dependently releases intracellular pneumolysin, which subsequently leads to lung injury. In this study, we hypothesized that pneumococcal autolysis induces the leakage of additional intracellular molecules that could increase the pathogenicity of S. pneumoniae. Liquid chromatography tandem-mass spectrometry analysis identified that chaperone protein DnaK, elongation factor Tu (EF-Tu), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were released with pneumococcal DNA by autolysis. We demonstrated that recombinant (r) DnaK, rEF-Tu, and rGAPDH induced significantly higher levels of interleukin-6 and tumor necrosis factor production in peritoneal macrophages and THP-1-derived macrophage-like cells via toll-like receptor 4. Furthermore, the DNA-binding activity of these proteins was confirmed by surface plasmon resonance assay. We demonstrated that pneumococcal DnaK, EF-Tu, and GAPDH induced the production of proinflammatory cytokines in macrophages, and might cause host tissue damage and affect the development of pneumococcal diseases.

Microbiological and Clinical Effects of Sitafloxacin and Azithromycin in Periodontitis Patients Receiving Supportive Periodontal Therapy.

Sitafloxacin (STFX) is a newly developed quinolone that has robust antimicrobial activity against periodontopathic bacteria. We previously reported that oral administration of STFX during supportive periodontal therapy was as effective as conventional mechanical debridement under local anesthesia microbiologically and clinically for 3 months. The aim of the present study was to examine the short-term and long-term microbiological and clinical effects of systemic STFX and azithromycin (AZM) on active periodontal pockets during supportive periodontal therapy. Fifty-one patients receiving supportive periodontal therapy were randomly allocated to the STFX group (200 mg/day of STFX for 5 days) or the AZM group (500 mg/day of AZM for 3 days). The microbiological and clinical parameters were examined until 12 months after the systemic administration of each drug. The concentration of each drug in periodontal pockets and the antimicrobial susceptibility of clinical isolates were also analyzed. The proportions of red complex bacteria, i.e., Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, which are the representative periodontopathic bacteria, were significantly reduced at 1 month and remained lower at 12 months than those at baseline in both the STFX and AZM groups. Clinical parameters were significantly improved over the 12-month period in both groups. An increase in the MIC of AZM against clinical isolates was observed in the AZM group. These results indicate that monotherapy with systemic STFX and AZM might be an alternative treatment during supportive periodontal therapy in patients for whom invasive mechanical treatment is inappropriate. (This study has been registered with the University Hospital Medical Information Network-Clinical Trials Registry [UMIN-CTR] under registration number UMIN000007834.).

UCP2 polymorphisms, daily step count, and number of teeth associated with all-cause mortality risk in Sado City: A hospital-based cohort study.

Objective: Uncoupling protein 2 (UCP2) is an ion/anion transporter in the mitochondrial inner membrane that plays a crucial role in immune response, regulation of oxidative stress, and cellular metabolism. UCP2 polymorphisms are linked to chronic inflammation, obesity, diabetes, heart disease, exercise efficiency, and longevity. Daily step count and number of teeth are modifiable factors that reduce mortality risk, although the role of UCP2 in this mechanism is unknown. This study aimed to assess the possible effects of UCP2 polymorphisms on the association between daily step count and number of teeth with all-cause mortality. Methods: This study was conducted as a cohort project involving adult Japanese outpatients at Sado General Hospital (PROST). The final number of participants was 875 (mean age: 69 y). All-cause mortality during thirteen years (from June 2008 to August 2021) was recorded. The functional UCP2 genotypes rs659366 and rs660339 were identified using the Japonica Array®. Survival analyses were performed using multivariate Cox proportional hazard models. Results: There were 161 deaths (mean observation period: 113 months). Age, sex, daily step count, and the number of teeth were significantly associated with mortality. In females, UCP2 polymorphisms were associated with mortality independent of other factors (rs659366 GA compared to GG + AA; HR = 2.033, p = 0.019, rs660339 C T compared to CC + TT; HR = 1.911, p = 0.029). Multivariate models, with and without UCP2 genotypes, yielded similar results. The interaction terms between UCP2 genotype and daily step count or number of teeth were not significantly associated with mortality. Conclusion: The effects of UCP2 polymorphisms on the association between daily step count or the number of teeth and all-cause mortality were not statistically significant. In females, UCP2 polymorphisms were significantly associated with all-cause mortality. Our findings confirmed the importance of physical activity and oral health and suggested a role of UCP2 in mortality risk independently with those factors.

Choline and geranate ionic liquid for subgingival biofilm control.

Periodontitis is a chronic inflammatory disease that causes destruction of the periodontium and eventual tooth loss. The priority in the periodontal treatment is to remove the subgingival biofilm. Chemical removal of biofilms using antimicrobial agents has been applied in clinical practice. However, their clinical effect is still limited because the agents must overcome biofilm's significant drug tolerance, which is primarily caused by the extracellular matrix, a physical barrier that attenuates drug diffusion. This study aimed to study the use of ionic liquids (ILs), a new class of biocompatible materials, for controlling subgingival biofilms because of their excellent permeability. Choline and geranate (CAGE) IL was tested for its highly potent antiseptic behavior and permeability. Antibacterial tests revealed that the significant efficacy of CAGE against periodontopathic microorganisms was derived from their ability to destroy cell membrane, as demonstrated by membrane permeability assay and transmission electron microscopy imaging. Antibiofilm tests using two pathogenic biofilm models revealed that CAGE exerted efficacy against the biofilm-embedded bacteria, conspicuously neutralized the biofilms, and eventually destroyed the biofilm structure. Furthermore, the penetration of CAGE into the biofilm was visually confirmed using confocal laser scanning microscopy. This study highlighted the potential of CAGE as a powerful antibiofilm therapeutic.

Protocols for collecting mouse PDL cells and bone marrow cells, differentiation, and data analysis.

Periodontal ligament cells (PDLCs) and macrophages in bone marrow cells have been widely used to investigate novel therapeutic agents to treat periodontitis. Here, we present a protocol for collecting primary mouse PDLCs and bone marrow cells. We detail steps for culturing and differentiation for both cell types and review data analysis for in vitro experiments using primary PDLCs and bone marrow cells. This protocol can be used to explore the impact of novel therapeutic agents using in vitro experiments. For complete details on the use and execution of this protocol, please refer to Sirisereephap et al.1.

Allyl isothiocyanate suppressed periodontal tissue destruction in mice via bacteriostatic and anti-inflammatory activities against Porphyromonas gingivalis.

OBJECTIVES: Allyl isothiocyanate (AITC) is a phytochemical that is abundantly present in cruciferous vegetables, such as wasabi and mustard. Among its pharmacological properties, it demonstrates anticancer, antifungal, and anti-inflammatory activities. This study aimed to investigate the functions of AITC against periodontopathic bacteria and its effects on a mouse model of periodontitis. DESIGN: The antimicrobial and antibiofilm functions of AITC were assessed against Porphyromonas gingivalis, Fusobacterium nucleatum, and Streptococcus mitis. To clarify its anti-inflammatory effects, macrophage-like cells from THP-1 were stimulated with P. gingivalis lipopolysaccharide (LPS), and the release of inflammatory cytokines was analyzed by ELISA. Experimental periodontitis was induced in 9-week-old mice by ligation and oral infection of P. gingivalis, and AITC was injected into the gingiva once daily for 8 days. Alveolar bone resorption was evaluated by measuring the exposed root area. Gene expressions in the periodontal tissue were analyzed via qPCR. RESULTS: AITC exerted weak bacteriostatic effects against P. gingivalis, inhibiting biofilm formation. AITC also impeded the production of interleukin-6 and tumor necrosis factor-α induced by P. gingivalis LPS. Additionally, transient receptor potential ankyrin 1(TRPA1) channel agonist inhibited the anti-inflammatory effects of AITC. In vivo, AITC inhibited alveolar bone destruction and decreased the gene transcription of Il6 in the periodontal tissue. CONCLUSION: AITC exerted weak bacteriostatic and anti-inflammatory effects against P. gingivalis, reducing alveolar bone destruction and suppressing the inflammatory response in experimental periodontitis. Therefore, AITC may serve as a valuable adjunct in controlling periodontal disease.

Effective degradation of various bacterial toxins using ozone ultrafine bubble water.

Infectious and foodborne diseases pose significant global threats, with devastating consequences in low- and middle-income countries. Ozone, derived from atmospheric oxygen, exerts antimicrobial effects against various microorganisms, and degrades fungal toxins, which were initially recognized in the healthcare and food industries. However, highly concentrated ozone gas can be detrimental to human health. In addition, ozonated water is unstable and has a short half-life. Therefore, ultrafine-bubble technology is expected to overcome these issues. Ultrafine bubbles, which are nanoscale entitles that exist in water for considerable durations, have previously demonstrated bactericidal effects against various bacterial species, including antibiotic-resistant strains. This present study investigated the effects of ozone ultrafine bubble water (OUFBW) on various bacterial toxins. This study revealed that OUFBW treatment abolished the toxicity of pneumolysin, a pneumococcal pore-forming toxin, and leukotoxin, a toxin that causes leukocyte injury. Silver staining confirmed the degradation of pneumolysin, leukotoxin, and staphylococcal enterotoxin A, which are potent gastrointestinal toxins, following OUFB treatment. In addition, OUFBW treatment significantly inhibited NF-κB activation by Pam3CSK4, a synthetic triacylated lipopeptide that activates Toll-like receptor 2. Additionally, OUFBW exerted bactericidal activity against Staphylococcus aureus, including an antibiotic-resistant strain, without displaying significant toxicity toward human neutrophils or erythrocytes. These results suggest that OUFBW not only sterilizes bacteria but also degrades bacterial toxins.

A novel macrolide-Del-1 axis to regenerate bone in old age.

Aging is associated with increased susceptibility to chronic inflammatory bone loss disorders, such as periodontitis, in large part due to the impaired regenerative potential of aging tissues. DEL-1 exerts osteogenic activity and promotes bone regeneration. However, DEL-1 expression declines with age. Here we show that systemically administered macrolide antibiotics and a non-antibiotic erythromycin derivative, EM-523, restore DEL-1 expression in 18-month-old ("aged") mice while promoting regeneration of bone lost due to naturally occurring age-related periodontitis. These compounds failed to induce bone regeneration in age-matched DEL-1-deficient mice. Consequently, these drugs promoted DEL-1-dependent functions, including alkaline phosphatase activity and osteogenic gene expression in the periodontal tissue while inhibiting osteoclastogenesis, leading to net bone growth. Macrolide-treated aged mice exhibited increased skeletal bone mass, suggesting that this treatment may be pertinent to systemic bone loss disorders. In conclusion, we identified a macrolide-DEL-1 axis that can regenerate bone lost due to aging-related disease.

The Pneumococcal Protein SufC Binds to Host Plasminogen and Promotes Its Conversion into Plasmin.

Streptococcus pneumoniae causes otitis media, sinusitis, and serious diseases such as pneumonia and bacteremia. However, the in vivo dynamics of S. pneumoniae infections and disease severity are not fully understood. In this study, we investigated pneumococcal proteins detected in the bronchoalveolar lavage fluid of an S. pneumoniae-infected mouse, which were assumed to be expressed during infection. Analysis of three proteins with unknown infection-related functions revealed that recombinant Fe-S cluster assembly ATP-binding protein (SufC) binds to the host plasminogen and promotes its conversion into plasmin. SufC was detected in the bacterial cell-surface protein fraction, but it had no extracellular secretory signal. This study suggests that S. pneumoniae releases SufC extracellularly through LytA-dependent autolysis, binding to the bacterial cell surface and host plasminogen and promoting its conversion into plasmin. The recruitment of plasmin by S. pneumoniae is considered useful for bacterial survival and spread, and SufC is suggested to facilitate this process.

Ozone ultrafine bubble water exhibits bactericidal activity against pathogenic bacteria in the oral cavity and upper airway and disinfects contaminated healthcare equipment.

Ozone is strong oxidizing agent that is applied in aqueous form for sanitation. However, ozonated water is unstable and has a short half-life. Ultrafine bubble technology is promising to overcome these issues. Ultrafine bubble is nanoscale bubble and can exist in water for a considerable duration of time. This study aims to investigate the application of ozone ultrafine bubble water (OUFBW) as a disinfectant. We produced an OUFBW generator which generates OUFBW containing 4-6 ppm of ozone. Thereafter, we examined the bactericidal activity of the OUFBW against various pathogenic bacteria in oral cavity and upper airway, including antibiotic-susceptible and antibiotic-resistant Streptococcus pneumoniae, Pseudomonas aeruginosa, Streptococcus mutans, Streptococcus sobrinus, Fusobacterium nucleatum, Prevotella intermedia, and Porphyromonas gingivalis. Exposure of planktonic culture of these bacterial species to OUFBW reduced viable bacteria by > 99% within 30s. Additionally, OUFBW exerted bactericidal activity against S. pneumoniae and P. aeruginosa adhered to toothbrush and gauze, respectively. We also observed disruption of bacterial cell wall of S. pneumoniae exposed to OUFBW by transmission electron microscope. Additionally, OUFB did not show any significant cytotoxicity toward the human gingival epithelial cell line Ca9-22. These results suggest that OUFBW exhibits bactericidal activity against broad spectrum of bacteria and has low toxicity towards human cells.

Osteoclastogenesis Inhibitor and Antioxidant Properties of Konjac Glucomannan in a Periodontitis Mice Model: An In Vivo Study.

Background: Periodontitis is an inflammatory disease caused by specific microorganisms that gradually damage the periodontal and tooth-supporting tissues, thereby reducing a person's quality of life. Periodontal disease is closely associated with high reactive oxygen species (ROS) levels, with a high receptor activator of nuclear factor kß ligand (RANKL)/osteoprotegerin (OPG) ratio. Konjac glucomannan (KGM) is produced from the porang root, which has several properties. For example, it can reduce oxidative stress. The current study analyzed the osteoclastogenesis inhibitory and antioxidant properties of KGM based on histomorphometric findings, RANKL/OPG ratio, and ROS levels in the Swiss Webster mouse periodontitis model. Methods: Eight-week-old male Swiss Webster mice were divided into the nonligation, nonligation + KGM, ligation + Porphyromonas gingivalis, and ligation + P. gingivalis + KGM groups. KGM suspension was administered for 14 days. Periodontitis induction was performed from 7th to 14th day. On the 14th day, maxillae, gingival, and gingival crevicular fluid samples were collected to assess the histomorphometry of bone damage, gene expression ratio of RANKL/OPG, and ROS protein levels. Results: The periodontitis group pretreated with KGM presented with significantly reduced alveolar bone damage, RANKL/OPG ratio, and ROS level than without KGM group. KGM treatment had no harmful/toxic effects in mice. Conclusion: Administration of KGM could act as an adjunctive in periodontal therapy by suppressing periodontal disease via osteoclastogenesis inhibitory and antioxidant properties.

Erythromycin Restores Osteoblast Differentiation and Osteogenesis Suppressed by Porphyromonas gingivalis Lipopolysaccharide.

The macrolide erythromycin (ERM) inhibits excessive neutrophil accumulation and bone resorption in inflammatory tissues. We previously reported that the expression of developmental endothelial locus-1 (DEL-1), an endogenous anti-inflammatory factor induced by ERM, is involved in ERM action. Furthermore, DEL-1 is involved in the induction of bone regeneration. Therefore, in this study, we investigated whether ERM exerts an osteoblastogenic effect by upregulating DEL-1 under inflammatory conditions. We performed in vitro cell-based mechanistic analyses and used a model of Porphyromonas gingivalis lipopolysaccharide (LPS)-induced periodontitis to evaluate how ERM restores osteoblast activity. In vitro, P. gingivalis LPS stimulation suppressed osteoblast differentiation and bone formation. However, ERM treatment combined with P. gingivalis LPS stimulation upregulated osteoblast differentiation-related factors and Del1, indicating that osteoblast differentiation was restored. Alveolar bone resorption and gene expression were evaluated in a periodontitis model, and the results confirmed that ERM treatment increased DEL-1 expression and suppressed bone loss by increasing the expression of osteoblast-associated factors. In conclusion, ERM restores bone metabolism homeostasis in inflammatory environments possibly via the induction of DEL-1.