Therapeutic effect of fluvastatin on medication-related osteonecrosis of the jaw.

BACKGROUND: Refractory jaw osteonecrosis that occurs in osteoporotic or cancer patients treated with bisphosphonates is called medication-related osteonecrosis of the jaw but its underlying mechanism is unclear. Statins, therapeutic agents for dyslipidemia, lower blood low-density lipoprotein cholesterol. Fluvastatin promotes the healing of tooth extraction sockets and reduces the risk of developing medication-related osteonecrosis of the jaw-like lesions. We used a rat model to investigate whether injecting fluvastatin at extraction sites promoted the healing of medication-related osteonecrosis of the jaw-like lesions. METHODS: Upper first molars of rats administered zoledronate and dexamethasone for 2 weeks were extracted. Two weeks after tooth extraction, rats with medication-related osteonecrosis of the jaw-like lesions (bone exposure) were included in this study. A single injection of fluvastatin was administered in the vicinity of the medication-related osteonecrosis of the jaw-like onset site in rats. RESULTS: The distance between the edges of the epithelia, the length of the necrotic bone exposed toward the oral cavity, the area of the necrotic bone, and the necrotic bone ratio were significantly smaller in the fluvastatin-administered group compared with the saline group. A single application of fluvastatin near the site of medication-related osteonecrosis of the jaw onset showed a tendency to close the epithelium, reduce necrotic bone, and form new bone, even when symptoms had already developed. CONCLUSION: This study suggests that a single topical administration of fluvastatin may be a novel treatment for medication-related osteonecrosis of the jaw.

Preventive effect of fluvastatin on the development of medication-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) occurs in patients undergoing oral surgery while medicated with bisphosphonate, denosumab or anti-angiogenic agents. We employed a MRONJ-like rat model to investigate whether injecting fluvastatin at extraction sites prevents MRONJ-like lesion. A MRONJ-like model was created by treating rats with zoledronate and dexamethasone, extracting teeth, and immediately injecting fluvastatin at the extraction site. The experimental group comprised three subgroups treated with low (0.1 mg/kg; FS-L), medium (1.0 mg/kg; FS-M) and high concentrations (10 mg/kg; FS-H) of fluvastatin. Necrotic bone exposure was significantly lower in the FS-M (p = 0.028) and FS-H (p = 0.041) groups than in the MRONJ group. The distance between the edges of the epithelial surfaces was significantly shorter in the FS-M (p = 0.042) and FS-H (p = 0.041) groups. The area of necrotic bone and the necrotic bone ratio were significantly smaller in the FS-H group (p = 0.041 and p = 0.042 respectively). Bone volume fraction calculated on µ-CT images was significantly larger in the FS-H group than in the MRONJ group (p = 0.021). Our findings suggest that a single local injection of fluvastatin following tooth extraction can potentially reduce the chance of developing MRONJ-like lesion in rats.

Effect of a Single Injection of Benidipine-Impregnated Biodegradable Microcarriers on Bone and Gingival Healing at the Tooth Extraction Socket.

Objective: A dihydropyridine-type calcium channel blocker, benidipine (BD), is extensively used in hypertension therapy. In vitro study reported BD promoting bone metabolism. We evaluated the effect of sustained release of BD-loaded poly(lactic-co-glycolic acid) (PLGA) microcarriers on the promotion of bone and gingival healing at an extraction socket in vivo. In addition, the effect of BD on osteoblasts, osteocytes, fibroblasts, and epithelial cells was evaluated in vitro. Approach: The maxillary first molar of rats was extracted. Next, PLGA microcarriers containing BD were directly injected into the gingivobuccal fold as a single dose. After injection, bone and soft-tissue healing was histologically evaluated. Effect of BD on proliferation, migration, and gene expression of gingival and bone cell was also examined in vitro. Results: After tooth extraction, BD significantly augmented bone volume and density, and also epithelial wound healing. During in vitro studies, BD promoted significant proliferation and migration of fibroblasts and epithelial cells. Real-time RT-PCR revealed that BD upregulated messenger RNA expression of Ahsg (alpha 2-HS glycoprotein) and Csf2 (colony-stimulating factor 2) in osteoblasts. Innovation: The prevention of bone and soft-tissue reduction associated with tooth extraction has been eagerly anticipated in the field of dentistry. This study first reported the effect of BD on extraction socket healing. Conclusion: A single dose of topically administered BD-loaded PLGA microcarriers promoted bone and soft-tissue healing at the extraction site of tooth.

Irregular sleep habits of parents are associated with increased sleep problems and daytime sleepiness of children.

Longitudinal studies in Japan indicate that nocturnal sleep onset has become later and sleep duration has been progressively shortened. This study aimed to investigate the relationship between sleep patterns and sleep problems among children, and to determine the association between parents and their children's sleep habits. Questionnaires about sleep problems and life habits were administered to families living in Tokyo metropolitan areas of Japan. We analyzed the data of pre-school-age (1-5 years old; n = 319, including 175 girls) and elementary school-age children (6-11 years; n = 217, including 116 girls) as well as their parents (402 mothers: 37.0 +/- 4.9 years, 402 fathers: 39.0 +/- 5.9 years). Subjects were categorized as morning (evening) type when they answered their lifestyle habit as "definitely or moderately morning (evening) type". Sleep was categorized into regular, irregular, and intermediate from the sleeping-waking regularity scores. The frequency of daytime dozing is significantly high in children with evening-irregular sleep. Moreover, mothers of children (aged 1-5 and 6-11 years) with evening-irregular sleep have significantly more irregular sleep habits than those of children with morning-regular sleep. Likewise, fathers of children (aged 1-5 years) with evening-irregular sleep have significantly more irregular sleep habits. Thus, irregular late bedtime of parents is associated with sleep problems, daytime sleepiness, and irregular dietary habits of children. Mothers' sleep habits have a stronger influence on their children's sleep than fathers'. Our study indicates the importance of promoting sleep hygiene that encourages healthy sleep for all family members.

An apoptotic inducer, aralin, is a novel type II ribosome-inactivating protein from Aralia elata.

We recently found that aralin, a novel cytotoxic protein consisting of two subunits, from Aralia elata selectively induces apoptosis in transformed cells as compared to normal cells. Here we report that aralin is a lectin specific for galactose (Gal) and its derivatives, and possesses RNA N-glycosidase activity as a new type II ribosome-inactivating protein (RIP). The RNA N-glycosidase activity of aralin was detected in cell-free and whole cell systems by the generation of an R-fragment from 28S rRNA. Coinciding with appearance of the R-fragment in aralin-treated cells, significant inhibition of protein synthesis was observed prior to the onset of apoptosis. Aralin-evoked cell death was efficiently repressed by the addition of Gal and its derivatives. Interestingly, melibiose preferentially protected normal cells from apoptosis as compared with transformed cells. Using rhodamine-coupled aralin, the aralin receptor could be clearly detected around the cell surface of transformed cells, but to a lesser extent on normal cells. Receptor binding was suppressed by Gal. These results indicate that aralin is incorporated into cells via its Gal-containing cell surface receptor and induces apoptosis through its RIP activity. Moreover, the expression level and/or structural changes of the aralin receptor may affect the sensitivity toward aralin.