Efficacy of perioperative oral care management in the prevention of surgical complications in 503 patients after pancreaticoduodenectomy for resectable malignant tumor: A multicenter retrospective analysis using propensity score matching.

BACKGROUND: Pancreaticoduodenectomy has been associated with a high mortality rate and significant postoperative morbidity. Recently, perioperative oral care management has been reported to be effective in preventing postoperative pneumonia and surgical site infection. In this study, we examined the effect of perioperative oral care management in reducing complications after pancreaticoduodenectomy, including surgical site infection. METHODS: This retrospective multicenter study included 503 patients who underwent pancreaticoduodenectomy at 8 facilities between January 2014 and December 2016. Among these, 144 received perioperative oral management by dentists and dental hygienists (oral management group), whereas the remaining 359 did not (control group). The oral care management program included oral health instructions, removal of dental calculus, professional mechanical tooth cleaning, removal of tongue coating, denture cleaning, instructions for gargling, and tooth extraction. The participants were matched using propensity scores to reduce background bias. Various factors were examined for correlation with the development of complications. RESULTS: The incidence of organ/space surgical site infection was significantly lower in the oral management group than in the control group (8.0% vs 19.6%, P = .005). Multivariable logistic regression analysis revealed that hypertension and lack of perioperative oral management were independent risk factors for organ/space surgical site infection. Lack of perioperative oral management had an odds ratio of 2.847 (95% confidence interval 1.335-6.071, P = .007). CONCLUSION: Perioperative oral care management reduces the occurrence of surgical site infections after pancreaticoduodenectomy and should be recommended as a strategy to prevent infections in addition to antibiotic use.

Hangeshashinto for prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized phase II study.

PURPOSE: Oral mucositis (OM) is a side effect associated with cancer treatment. Hangeshashinto (HST), a Kampo medicine, was originally prescribed to treat diarrhea, gastritis, and stomatitis. Several reports have described the effects of HST for OM induced by chemotherapy in patients with gastric or colorectal cancer. In this study, the effects of HST for prevention of OM were investigated in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty patients scheduled to receive allogeneic grafts were enrolled from July 2020 to December 2021. They were randomly assigned to two groups and instructed to wash their mouth using HST dissolved in saline solution or using only saline solution three times a day. The observation period was from the initiation date of the conditioning regimen to the date of engraftment, and the end point was the incidence of OM. RESULTS: Eighteen patients developed OM, the most severe of which was Grade (G)3. There was no significant difference in the incidence of OM between the HST group and the control group. However, a negative correlation tended to be observed between the duration using HST use and the duration of OM (G2-3: P = 0.027, G3: P = 0.047). CONCLUSIONS: The present study demonstrated that HST use did not clearly inhibit onset of OM but showed a tendency to inhibit OM exacerbation. However, further studies are necessary to fully understand the effects of HST on OM in patients undergoing HSCT. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials on 7 May 2020 (jRCTs071200012).

Effects of anti-mouse RANKL antibody on orthodontic tooth movement in mice.

Background/purpose: Orthodontic tooth movement is achieved by alveolar bone remodeling, and therefore the balance of bone resorption and formation is important. Receptor activator of nuclear factor-κB ligand (RANKL) plays a crucial role in bone resorption. We previously reported that tumor necrosis factor-α (TNF-α) is also important in bone resorption during tooth movement. In this study, we focused on bone and root resorption during orthodontic tooth movement in mice using anti-mouse RANKL antibody (anti-mRANKL ab). Materials and methods: Anti-mRANKL ab was administered intraperitoneally to mice that subsequently underwent orthodontic tooth movement. After 10 days, tissues around the moved teeth were histologically evaluated. To confirm the effects of anti-mRANKL ab on TNF-α induced bone resorption, TNF-α was administered with and without anti-mRANKL ab into the supracalvaria and the sutures of the calvaria were histologically evaluated. Results: Orthodontic tooth movement was suppressed in mice treated with anti-mRANKL ab. Root resorption was observed after orthodontic tooth movement, but not in mice treated with anti-mRANKL ab. In the calvarial experiment, the number of TRAP-positive cells in the calvarial sutures was lower in mice administered TNF-α with anti-mRANKL ab than in mice administered TNF-α alone. Conclusion: Our findings suggest that anti-mRANKL ab suppressed orthodontic tooth movement. This needs to be considered when orthodontic tooth movement is required in patients using anti-RANKL antibody.

A preliminary study of suppression of candida infection by miconazole mucoadhesive tablets in oral or oropharyngeal cancer patients undergoing radiotherapy.

Elevated numbers of candida in the oral cavity often lead to oral candidiasis development in patients undergoing radiotherapy for oral or oropharyngeal cancer. This study aimed to verify the effect of miconazole mucoadhesive tablets on suppression of oral candida infection during radiotherapy. For this preliminary interventional study, miconazole mucoadhesive tablets were attached to the oral mucosa for 14 days from when grade 2 oral mucositis appeared in patients with oral or oropharyngeal cancer receiving radiotherapy, and the incidence of oral candidiasis was investigated. Various clinical factors were examined; univariate and multivariate Cox regression analyses were performed to investigate and compare the efficacy of this drug in preventing oral candidiasis with results of our previous study as historical control. Miconazole mucoadhesive tablets were administered to 18 patients, and oral candidiasis was observed in one patient (5.6%) after treatment completion. Among 144 historical control patients, 43 (29.9%) developed oral candidiasis. Multivariate Cox regression showed that miconazole mucoadhesive tablets significantly reduced oral candidiasis development during radiotherapy (p = 0.049, Hazard ratio 0.136, 95% confidence interval 0.019-0.994). This preliminary study suggests the efficacy of miconazole mucoadhesive tablets in preventing oral candidiasis in oral or oropharyngeal cancer patients treated with radiotherapy.Trial registration: Japan Registry of Clinical Trials (jRCT), jRCTs071190023. Registered 3 September, 2019.

Preventive effects of betamethasone valerate ointment for radiation-induced severe oral mucositis in patients with oral or oropharyngeal cancer: protocol for a multicentre, phase II, randomised controlled trial (Bet-ROM study).

INTRODUCTION: This is a randomised, multi-centre, open-label, phase II study to evaluate the efficacy of betamethasone valerate ointment on radiation-induced oral mucositis in patients with head and neck cancer undergoing concomitant radiotherapy with cisplatin or cetuximab. METHODS AND ANALYSIS: The trial will take place at seven hospitals in Japan. Patients will be randomised (1:1) into betamethasone and control groups after the occurrence of grade 1 oral mucositis. In the betamethasone group, patients will use betamethasone valerate ointment five times a day, in addition to usual oral hygiene guidance. The primary endpoint is the incidence and onset time of grade 3 oral mucositis. The secondary endpoints are the incidence and onset time of grade 2 oral mucositis, incidence and onset time of oral candidiasis, completion of radiation therapy and adverse events. Target accrual is 102 patients with a two-sided type I error rate of 5% and 80% power to detect an 80% risk reduction in the incidence of grade 3 oral mucositis. ETHICS AND DISSEMINATION: This study was approved by the Clinical Research Review Board of Nagasaki University (No. CRB20-009). All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publication. The datasets generated during the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: jRCTs071200013.

Effects of a bioadhesive barrier-forming oral liquid on pain due to radiation-induced oral mucositis in patients with head and neck cancer: A randomized crossover, preliminary study.

BACKGROUND/PURPOSE: Bioadhesive barrier-forming oral liquid, is a recently developed medical material for the management of pain caused by oral mucositis associated with cancer radiotherapy or chemotherapy. The purpose of this study was to evaluate the effectiveness of this liquid in relieving pain resulting from radiation-induced oral mucositis in patients with head and neck cancer. MATERIALS AND METHODS: This randomized, crossover trial investigated the analgesic effects of bioadhesive barrier-forming oral liquid using dexamethasone ointment as a control. Fifteen patients with mild or moderate pain due to radiation-induced oral mucositis were randomly assigned to two groups. Group A applied dexamethasone ointment once on day 1, had a wash-out period on day 2, and used bioadhesive barrier-forming oral liquid once on day 3. Conversely, group B used bioadhesive barrier-forming oral liquid on day 1, had a wash-out period on day 2, and applied dexamethasone ointment once on day 3. The effectiveness in relieving pain was compared between the two groups. RESULTS: One patient reported nausea immediately after the application of bioadhesive barrier-forming oral liquid and was therefore excluded from the analysis. Dexamethasone ointment and bioadhesive barrier-forming oral liquid relieved pain in 85.7% and 71.4% patients, respectively (p = 0.682). Nine patients wished to continue dexamethasone ointment after the study, while only five wished to continue bioadhesive barrier-forming oral liquid. CONCLUSION: Our findings suggest that the analgesic effect of bioadhesive barrier-forming oral liquid is comparable or inferior to that of dexamethasone ointment in patients with radiation-induced oral mucositis. Further studies are needed to verify these findings.

Evaluation of the efficacy of low concentration fluoride gel using custom trays to prevent radiation-related dental caries in patients with head and neck cancer: protocol for a randomised controlled phase III trial (FluCar study).

INTRODUCTION: The present study is a randomised, multicentre, open-label, phase III study, to evaluate the efficacy of low concentration of fluoride gel, applied using custom trays, in preventing radiation-related dental caries in patients with head and neck cancer who have undergone or are undergoing radiotherapy. METHODS AND ANALYSIS: Patients will be randomised into fluoride and control groups (1:1 ratio). In the fluoride group, patients will wear custom trays loaded with 0.145% fluoride gel after brushing every night while sleeping. In the control group, patients will receive oral hygiene instructions as usual. Patients in both the groups will be followed up every 3 months for 1 year. The primary endpoint is the incidence of newly developed dental caries. Target accrual is 80 patients with a two-sided type I error rate of 5% and 80% power to detect 80% risk reduction. ETHICS AND DISSEMINATION: This study was approved by the Clinical Research Review Board in Nagasaki University The protocol of this study was registered at Japan Registry of Clinical Trials (jRCT) and University hospital Medical Information Network Clinical Trials Registry (UMIN). The datasets generated during the current study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBERS: jRCTs 072190039 and UMIN000041426.

Risk factors associated with the development of aspiration pneumonia in patients receiving radiotherapy for head and neck cancer: retrospective study.

BACKGROUND: Patients with head and neck cancer who are receiving radiotherapy can develop aspiration pneumonia. Determination of the incidence of aspiration pneumonia and the associated risk factors could facilitate the identification of high-risk patients. METHODS: In this retrospective study, we determined the incidence of aspiration pneumonia in 357 patients receiving radiotherapy along with oral care for head and neck cancer. We also performed univariate and multivariable logistic regression analyses to investigate the risk factors for this complication. RESULTS: The incidence of aspiration pneumonia was 17.6%. Hypopharyngeal cancer, grade 3 oral mucositis, and nasogastric tube feeding were independent risk factors. Moreover, the development of aspiration pneumonia was one of the major effects on the discontinuation of radiotherapy. CONCLUSION: Approximately, one-sixth of the patients developed aspiration pneumonia despite appropriate oral care during radiotherapy for head and neck cancer. Aspiration pneumonia during radiotherapy could adversely affect head and neck cancer management.

Prevention of dental caries by regular overnight application of a low-concentration fluoride gel loaded in a custom tray in patients undergoing radiotherapy for head and neck cancer: A preliminary study.

BACKGROUND: Some studies have reported topical application of 1.0%-2.0% fluoride gel in a custom tray for 4-5 minutes every day for the prevention of radiation-related dental caries. However, in Japan, the concentration of fluoride used by patients is limited to less than 0.15%. The efficacy of a low-concentration fluoride gel in a custom tray for the prevention of radiation-related dental caries has not been investigated. Methods and Material: In this preliminary study, we enrolled 13 patients with head and neck cancer who underwent radiotherapy. They wore a custom tray containing 0.145% sodium fluoride gel during sleep every night and were examined for newly developed dental caries 1 year later. Results: No new dental caries were found in the 13 patients 1 year after radiotherapy, and no adverse events were observed. CONCLUSIONS: We conclude that low-concentration fluoride gel in a custom tray during sleep could prevent radiation-related dental caries, and we plan to conduct a multi-center phase III randomized controlled trial to examine the efficacy of this method for the prevention of radiation-related dental caries.

Effects of the changes in the condylar long axis angle and condylar position on temporomandibular symptoms after intraoral vertical ramus osteotomy: a preliminary study.

OBJECTIVE: This study was conducted to characterize the effects of the changes in the condylar long axis and position on temporomandibular symptoms with respect proximal segment position after intraoral vertical ramus osteotomy (IVRO). STUDY DESIGN: Twenty Japanese patients with diagnosed jaw deformity underwent IVRO without internal fixation. Long-term changes in condylar long axis and position were assessed during postoperative follow-up examinations by using computed tomography, and t tests were performed for comparison. In addition, changes in temporomandibular symptoms were examined. RESULTS: The degree of axial rotation of the proximal segment changed significantly when the proximal segment was located laterally. Downward changes in condylar position significantly differed when the proximal segment was located posterolaterally. Forward changes in condylar position significantly differed when the proximal segment was located laterally; moreover, when the proximal segment was located laterally, temporomandibular symptoms disappeared. CONCLUSIONS: Lateral location of the proximal segment may be an important factor in the positive effects of IVRO, with respect to temporomandibular symptoms.

Effects of perioperative oral care on prevention of postoperative pneumonia after lung resection: Multicenter retrospective study with propensity score matching analysis.

BACKGROUND: Postoperative pneumonia can be a fatal complication that may occur after lung resection in cancer patients. Some reports have shown that the incidence of postoperative pneumonia is decreased after esophageal surgery by perioperative oral care; however, there exist no data to suggest that a lack of perioperative oral care can be a risk factor for postoperative pneumonia after lung resection. To investigate the association between the preventive effect of oral care and postoperative pneumonia, we conducted a multicenter, retrospective study of lung cancer patients who underwent lung resection. METHODS: Between January 2014 and December 2016, a total of 721 patients underwent lung resections at 1 of the 6 hospitals included in our study. Among 721 patients, 280 (38.8%) received perioperative oral care, and the remaining 441 (61.2%) did not receive any such care. Propensity score matching was performed to minimize selection biases associated with the comparison of retrospective data between the oral care and control groups. RESULTS: Of the 721 patients, 54 (7.5%) experienced postoperative pneumonia involving 13 of the 280 patients (4.6%) in the oral care group and 41 of the 441 patients (9.3%) in the control group (P = .02). On propensity score analysis, a significant difference was also found between oral care intervention and incidence of postoperative pneumonia (P = .002). CONCLUSION: Our results suggest that perioperative oral care is an effective method to decrease the occurrence of postoperative pneumonia in patients who have undergone lung resection.

A retrospective study of factors associated with the development of oral candidiasis in patients receiving radiotherapy for head and neck cancer: Is topical steroid therapy a risk factor for oral candidiasis?

The aims of this study were to investigate the incidence and risk factors for oral candidiasis in patients receiving radiotherapy for head and neck cancer, and to determine the influence of topical steroid therapy on the development of oral candidiasis.We conducted a retrospective study of 300 patients receiving radiotherapy to the head and neck region. The primary endpoint was the incidence of oral candidiasis during radiotherapy. Associations between the incidence of oral candidiasis and various clinical factors were investigated. The cumulative incidence rate of oral candidiasis was calculated using the Kaplan-Meier method and analyzed by the log-rank test and Cox regression. Propensity score-matched analysis was used to assess the influence of topical steroid therapy on the development of oral candidiasis.Oral candidiasis occurred in 75 (25.0%) of the 300 patients. Multivariate analysis identified minimum lymphocyte count and severity of oral mucositis during radiotherapy as independent risk factors for the development of oral candidiasis. Topical steroid therapy for oral mucositis was not associated with the incidence of oral candidiasis according to multivariate and propensity score matching analyses.Oral candidiasis was associated with the suppression of the host's immunity and severe oral mucositis, but not topical steroid therapy. Proper oral health care during radiotherapy and the prevention of severe oral mucositis may reduce the incidence of oral candidiasis.

Sanguiin H-6, a constituent of Rubus parvifolius L., inhibits receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis and bone resorption in vitro and prevents tumor necrosis factor-α-induced osteoclast formation in vivo.

BACKGROUND: Osteoclasts are multinucleated bone-resorbing cells that differentiate in response to receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). Enhanced osteoclastogenesis contributes to bone diseases, such as osteoporosis and rheumatoid arthritis. Rubus parvifolius L. is traditionally used as an herbal medicine for rheumatism; however, its detailed chemical composition and the molecular mechanisms responsible for its biological action have not been elucidated. PURPOSE: To investigate the mechanisms by which R. parvifolius L. extract and its major constituent sanguiin H-6, inhibit osteoclastogenesis and bone resorption. METHODS: Cell proliferation, cell differentiation, and bone resorption were detected in vitro. Inhibition of signaling pathways, marker protein expression, and protein nuclear translocation were evaluated by western blot analysis. Tumor necrosis factor-α (TNF-α)-mediated osteoclastogenesis was examined in vivo. RESULTS: R. parvifolius L. extract inhibited the bone-resorption activity of osteoclasts. In addition, sanguiin H-6 markedly inhibited RANKL-induced osteoclast differentiation and bone resorption, reduced reactive oxygen species production, and inhibited the phosphorylation of inhibitor of NF-κB alpha (IκBα) and p38 mitogen-activated protein kinase. Sanguiin H-6 also decreased the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), cathepsin K, and c-Src. Moreover, sanguiin H-6 inhibited the nuclear translocation of NFATc1, c-Fos, and NF-κB in vitro, as well as TNF-α-mediated osteoclastogenesis in vivo. CONCLUSIONS: Our data revealed that R. parvifolius L. has anti-bone resorption activity and suggest that its constituent, sanguiin H-6, can potentially be used for the prevention and treatment of bone diseases associated with excessive osteoclast formation and subsequent bone destruction.

IL-12 Inhibits Lipopolysaccharide Stimulated Osteoclastogenesis in Mice.

Lipopolysaccharide (LPS) is related to osteoclastogenesis in osteolytic diseases. Interleukin- (IL-) 12 is an inflammatory cytokine that plays a critical role in host defense. In this study, we investigated the effects of IL-12 on LPS-induced osteoclastogenesis. LPS was administered with or without IL-12 into the supracalvariae of mice, and alterations in the calvarial suture were evaluated histochemically. The number of osteoclasts in the calvarial suture and the mRNA level of tartrate-resistant acid phosphatase (TRAP), an osteoclast marker, were lower in mice administered LPS with IL-12 than in mice administered LPS alone. The serum level of tartrate-resistant acid phosphatase 5b (TRACP 5b), a bone resorption marker, was also lower in mice administered LPS with IL-12 than in mice administered LPS alone. These results revealed that IL-12 might inhibit LPS-induced osteoclastogenesis and bone resorption. In TdT-mediated dUTP-biotin nick end-labeling (TUNEL) assays, apoptotic changes in cells were recognized in the calvarial suture in mice administered LPS with IL-12. Furthermore, the mRNA levels of both Fas and FasL were increased in mice administered LPS with IL-12. Taken together, the findings demonstrate that LPS-induced osteoclastogenesis is inhibited by IL-12 and that this might arise through apoptotic changes in osteoclastogenesis-related cells induced by Fas/FasL interactions.

Effect of cytokines on osteoclast formation and bone resorption during mechanical force loading of the periodontal membrane.

Mechanical force loading exerts important effects on the skeleton by controlling bone mass and strength. Several in vivo experimental models evaluating the effects of mechanical loading on bone metabolism have been reported. Orthodontic tooth movement is a useful model for understanding the mechanism of bone remodeling induced by mechanical loading. In a mouse model of orthodontic tooth movement, TNF-α was expressed and osteoclasts appeared on the compressed side of the periodontal ligament. In TNF-receptor-deficient mice, there was less tooth movement and osteoclast numbers were lower than in wild-type mice. These results suggest that osteoclast formation and bone resorption caused by loading forces on the periodontal ligament depend on TNF-α. Several cytokines are expressed in the periodontal ligament during orthodontic tooth movement. Studies have found that inflammatory cytokines such as IL-12 and IFN-γ strongly inhibit osteoclast formation and tooth movement. Blocking macrophage colony-stimulating factor by using anti-c-Fms antibody also inhibited osteoclast formation and tooth movement. In this review we describe and discuss the effect of cytokines in the periodontal ligament on osteoclast formation and bone resorption during mechanical force loading.

Immunological reaction in TNF-α-mediated osteoclast formation and bone resorption in vitro and in vivo.

Tumor necrosis factor- α (TNF- α ) is a cytokine produced by monocytes, macrophages, and T cells and is induced by pathogens, endotoxins, or related substances. TNF- α may play a key role in bone metabolism and is important in inflammatory bone diseases such as rheumatoid arthritis. Cells directly involved in osteoclastogenesis include macrophages, which are osteoclast precursor cells, osteoblasts, or stromal cells. These cells express receptor activator of NF- κ B ligand (RANKL) to induce osteoclastogenesis, and T cells, which secrete RANKL, promote osteoclastogenesis during inflammation. Elucidating the detailed effects of TNF- α on bone metabolism may enable the identification of therapeutic targets that can efficiently suppress bone destruction in inflammatory bone diseases. TNF- α is considered to act by directly increasing RANK expression in macrophages and by increasing RANKL in stromal cells. Inflammatory cytokines such as interleukin- (IL-) 12, IL-18, and interferon- γ (IFN- γ ) strongly inhibit osteoclast formation. IL-12, IL-18, and IFN- γ induce apoptosis in bone marrow cells treated with TNF- α in vitro, and osteoclastogenesis is inhibited by the interactions of TNF- α -induced Fas and Fas ligand induced by IL-12, IL-18, and IFN- γ . This review describes and discusses the role of cells concerned with osteoclast formation and immunological reactions in TNF- α -mediated osteoclastogenesis in vitro and in vivo.

Inhibitory effect of interferon-γ on experimental tooth movement in mice.

The aim of this study was to investigate the effects of interferon (IFN)-γ on experimental tooth movement in mice using a murine experimental tooth movement model. An Ni-Ti closed-coil spring was inserted between the upper-anterior alveolar bones and the upper-left first molars in mice. We evaluated the relationship between local Ifn-γ mRNA levels and orthodontic tooth movement. In other experiments, IFN-γ was injected adjacent to each first molar every other day during tooth movement. After 12 days, the amount of tooth movement was measured. Tartrate-resistant acid phosphatase (TRAP)-positive cells at the pressure side of each experimental tooth were counted as osteoclasts. Local Ifn-γ mRNA expression increased with orthodontic tooth movement. The number of TRAP-positive cells increased on the pressure side of the first molar. In contrast, the degree of tooth movement and the number of TRAP-positive cells on the pressure side in IFN-γ-injected mice were less than those of control mice. IFN-γ was induced in experimental tooth movement, and could inhibit mechanical force-loaded osteoclastogenesis and tooth movement. These results suggest that IFN-γ might be useful in controlling orthodontic tooth movement because of its inhibitory action on excessive osteoclastogenesis during this movement.

Inhibitory effects of IL-12 on experimental tooth movement and root resorption in mice.

OBJECTIVE: Interleukin (IL)-12 is an important cytokine for innate and adaptive immunity. We previously reported that IL-12 inhibits tumour necrosis factor (TNF)-α-mediated osteoclast formation by inducing apoptosis. We also reported that TNF-α plays an important role in mechanical loading-induced osteoclast formation and bone resorption during orthodontic tooth movement. In this study, we investigated the effects of IL-12 on mechanical tooth movement in mice. DESIGN: A Ni-Ti closed coil spring was inserted between the upper incisors and the upper left first molar in mice. IL-12 was injected locally adjacent to the first molar every other day during the experimental period, at doses varying from 0 to 1.5µg/day. After 12 days, the animals were killed and their jaws were processed for histological evaluation using tartrate-resistant acid phosphatase (TRAP) and TdT-mediated dUTP-biotin nick end-labelling (TUNEL) staining, and measurements of the root resorption area. RESULTS: In the IL-12-treated mice, tooth movement and root resorption appeared to be reduced. In TUNEL-stained sections, many apoptotic cells were recognized on the pressure side in the IL-12-treated mice. CONCLUSIONS: Our findings suggest that IL-12 inhibits not only mechanical tooth movement, but also root resorption during orthodontic tooth movement. These findings may arise through apoptosis induced by IL-12.

IL-12- and IL-18-mediated, nitric oxide-induced apoptosis in TNF-α-mediated osteoclastogenesis of bone marrow cells.

TNF-α has been recognized as an important factor for osteoclastogenesis and plays an important role in bone resorption under pathological conditions. IL-12 and IL-18, which are T-cell mediators, are also important inflammatory cytokines. We have reported that IL-12 and IL-18 induce apoptosis in bone marrow cells treated with TNF-α in vitro and that osteoclastogenesis is inhibited by the interaction of TNF-α-induced Fas and the IL-12-induced Fas ligand (FasL). However, the anti-FasL antibody could not completely inhibit apoptosis. Therefore, it is possible that IL-12 and IL-18 may also trigger some other apoptotic mechanisms. Nitric oxide (NO) may act as a mediator of the apoptotic effect. In this study, we examined whether NO causes the IL-12- and IL-18-induced apoptosis of bone marrow cells in TNF-α-mediated osteoclast formation. We found that NO production was induced in bone marrow cells cultured with IL-12 and IL-18 in the presence of TNF-α. When bone marrow cells were cultured with TNF-α, osteoclasts were formed. In contrast, when bone marrow cells were cultured with both TNF-α and IL-12 or IL-18, the adherent cells were induced to undergo apoptosis. Apoptosis was partially inhibited when bone marrow cells were treated with NO synthase inhibitors. Furthermore, IL-12 and IL-18 synergistically induced cell death and upregulated NO production in the presence of TNF-α. These results indicate that the simultaneous effects of TNF-α and IL-12 or IL-18 on bone marrow cells induce apoptosis and that apoptosis is induced by the production of NO.

IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions.

Cytokines secreted by T cells play a pivotal role in inflammatory bone destruction. Tumor necrosis factor-α (TNF-α) is a major proinflammatory cytokine produced by macrophages following T cell activation, and directly promotes osteoclast differentiation resulting in accelerated bone resorption. Interferon-γ (IFN-γ) attenuates RANKL-initiated cellular signals through osteoclast formation and counterbalances aberrant bone resorption. With respect to this crosstalk during osteoclastogenesis, the direct interruption of IFN-γ in TNF-α-induced osteoclast formation still requires elucidation. We have demonstrated that IFN-γ directly inhibits osteoclastogenesis induced by TNF-α stimulation and accelerates apoptosis mediated by Fas/Fas ligand signals. There were a decreased number of osteoclasts and reduced mRNA levels encoding Nfatc1 in cultured bone marrow macrophages. Apoptotic responses of cultured cells were observed, with accelerated nuclear fragmentation in osteoclast precursor cells and increased FasL mRNA levels in bone marrow cells stimulated with TNF-α evident. IFN-γ reduced the level of osteoclastogenesis in response to TNF-α treatment in vivo. IFN-γ inhibited TNF-α-induced osteoclastogenesis in mice with T cells that had been exposed to anti-CD4 and -CD8 antibodies. These results provide evidence that IFN-γ directly inhibits osteoclastogenesis and induces cells apoptosis by Fas/FasL signals, leading to the indirect regulation of bone resorption, which is required for protective roles in bone destruction at an inflammation site.