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Introduction: The incidence of obesity has dramatically increased worldwide. Obesity has been shown to exacerbate the progression of periodontal disease. Studies suggest a sex difference in periodontitis, whereby males are more sensitive to periodontal inflammation compared to females. Aim: In the current study, it was hypothesized that obesity drives periodontal inflammation and bone loss in both sexes. Methodology: Utilizing leptin receptor mutant (SSLepR mutant) rats as a genetic model of obesity, 11–12-week-old male and female lean Dahl salt-sensitive (SS) rats and obese SSLepR mutant rats were used to investigate sex differences in obesity-induced periodontal inflammation. Results: Body weight, insulin, hemoglobin A1c and cholesterol levels were significantly elevated in the obese SSLepR mutant strain vs. the lean SS strain within the same sex. Sex differences in body weight and plasma hemoglobin A1c were only observed in obese SSLepR mutant rats, with males having significantly greater body weight and hemoglobin A1c vs. females. Plasma thiobarbituric acid reactive substances (TBARs) and monocyte chemoattractant protein-1 (MCP-1), markers of systemic oxidative stress and inflammation, respectively, were significantly elevated in obese SSLepR mutant rats vs. lean SS rats, with no sex differences in these parameters in either rat strains. Although micro-CT analyses of the maxillary first molar alveolar bone from obese SSLepR mutant rats revealed no evidence of bone loss and/or sex differences, immuno-histochemical analysis revealed significant elevations in periodontal IL-6 and decreases in IL-10 in obese SSLepR mutant rats vs. lean SS rats, with no apparent sex differences in these parameters. Conclusions: Obesity increases systemic and periodontal inflammation, without evidence of bone loss or apparent sex differences in SSLepR mutant rats. [ABSTRACT FROM AUTHOR]

Aims Cyclooxygenase-2–derived prostaglandin E2 (PGE2) is thought to promote vascular intimal hyperplasia (IH). It has been reported that the PGE2 receptor EP4 is upregulated in injured vessels and that EP4 signalling in vascular smooth muscle cells (VSMCs) promotes IH. In contrast, EP4 in endothelial cells has been demonstrated to restrain IH. We aimed to investigate spatiotemporal expression of EP4 and whether modulating EP4 signalling could be a viable therapeutic strategy. Methods and results We generated EP4 reporter mice (Ptger4 -IRES-nlsLacZ) and found temporary but prominent EP4 expression in VSMCs of the proliferative neointima 2 weeks after femoral artery wire injury. Injury-induced IH was diminished in VSMC-targeted EP4 heterozygous deficient mice (Ptger4 fl/+; SM22 - Cre) 2 and 4 weeks after vascular injury compared to that in SM22 - Cre , whereas injury-induced IH was exacerbated in VSMC-targeted EP4-overexpressing mice (Ptger4 -Tg) compared to controls (non-Tg). We then investigated the downstream signalling of EP4 in VSMCs. Stimulation of EP4 increased mRNA and protein levels of the glycoprotein fibulin-1 in Ptger4 -Tg VSMCs. Fibulin-1C recombinant proteins increased VSMC proliferation and migration through transforming growth factor (TGF)- β/Smad3, and EP4-mediated proliferation and migration were attenuated in Fbln1 fl/fl; SM22 - Cre VSMCs and in CRISPR/Cas9-mediated Fbln1 knockdown in Ptger4 -Tg VSMCs. We generated multiple deletion mutants of fibulin-1C and found that EGF-like modules 6–8 appear to be involved in fibulin-1-mediated proliferation. Among binding partners of fibulin-1, extracellular matrix protein 1 (ECM1) was also upregulated by EP4 stimulation, and fibulin-1C and ECM1 proteins additively enhanced VSMC proliferation and migration. Injury-induced IH was attenuated in VSMC-targeted fibulin-1 deletion mice (Fbln1 fl/fl; SM22 - Cre) compared to Fbln1 fl/fl. Furthermore, systemic EP4 antagonist administration reduced injury-induced IH in wild-type mice. Conclusion EP4 was upregulated in VSMCs of proliferative IH, and EP4 signalling promoted IH, at least in part through fibulin-1. An EP4 antagonist might be considered as a therapeutic strategy for IH. [ABSTRACT FROM AUTHOR]

Excessive fluoride ingestion during tooth development can cause dental fluorosis. Previously, we reported that fluoride activates histone acetyltransferase (HAT) to acetylate p53, promoting fluoride toxicity in mouse ameloblast-like LS8 cells. However, the roles of HAT and histone acetylation status in fluoride-mediated gene expression remain unidentified. Here, we demonstrate that fluoride-mediated histone modification causes gene expression alterations in LS8 cells. LS8 cells were treated with or without fluoride followed by ChIP-Seq analysis of H3K27ac. Genes were identified by differential H3K27ac peaks within ±1 kb from transcription start sites. The levels of mRNA of identified genes were assessed using rea-time PCR (qPCR). Fluoride increased H3K27ac peaks associated with Bax, p21, and Mdm2 genes and upregulated their mRNA levels. Fluoride decreased H3K27ac peaks and p53, Bad, and Bcl2 had suppressed transcription. HAT inhibitors (Anacardic acid or MG149) suppressed fluoride-induced mRNA of p21 and Mdm2, while fluoride and the histone deacetylase (HDAC) inhibitor sodium butyrate increased Bad and Bcl2 expression above that of fluoride treatment alone. To our knowledge, this is the first study that demonstrates epigenetic regulation via fluoride treatment via H3 acetylation. Further investigation is required to elucidate epigenetic mechanisms of fluoride toxicity in enamel development. [ABSTRACT FROM AUTHOR]

This study's objective was to investigate how contractile strength loss associated with a volumetric muscle loss (VML) injury affects the adjacent tibial bone structural and functional properties in male C57BL/6J mice. Mice were randomized into one of two experimental groups: VML‐injured mice that were injured at age 12 weeks and aged to 20 weeks (8 weeks postinjury, VML) and 20‐week‐old age‐matched uninjured mice (Uninjured‐20). Tibial bone strength, mid‐diaphysis cortical geometry, intrinsic material properties, and metaphyseal trabecular bone structure were assessed by three‐point bending and microcomputed tomography (µCT). The plantar flexor muscle group (gastrocnemius, soleus, plantaris) was analyzed for its functional capacities, that is, peak‐isometric torque and peak‐isokinetic power. VML‐injured limbs had 25% less peak‐isometric torque and 31% less peak‐isokinetic power compared to those of Uninjured‐20 mice (p < 0.001). Ultimate load, but not stiffness, was significantly less (10%) in tibias of VML‐injured limbs compared to those from Uninjured‐20 (p = 0.014). µCT analyses showed cortical bone thickness was 6% less in tibias of VML‐injured limbs compared to Uninjured‐20 (p = 0.001). Importantly, tibial bone cross‐section moment of inertia, the primary determinant of bone ultimate load, was 16% smaller in bones of VML‐injured limbs compared to bones from Uninjured‐20 (p = 0.046). Metaphyseal trabecular bone structure was also altered up to 23% in tibias of VML‐injured limbs (p < 0.010). These changes in tibial bone structure and function after a VML injury occur during a natural maturation phase between the age of 12 and 20 weeks, as evidenced by Uninjured‐20 mice having greater tibial bone size and strength compared to uninjured‐aged 12‐week mice. [ABSTRACT FROM AUTHOR]

This study's objective was to investigate the extent to which two different levels of low‐intensity vibration training (0.6 g or 1.0 g) affected musculoskeletal structure and function after a volumetric muscle loss (VML) injury in male C57BL/6J mice. All mice received a unilateral VML injury to the posterior plantar flexors. Mice were randomized into a control group (no vibration; VML‐noTX), or one of two experimental groups. The two experimental groups received vibration training for 15‐min/day, 5‐days/week for 8 weeks at either 0.6 g (VML‐0.6 g) or 1.0 g (VML‐1.0 g) beginning 3‐days after induction of VML. Muscles were analyzed for contractile and metabolic adaptations. Tibial bone mechanical properties and geometric structure were assessed by a three‐point bending test and microcomputed tomography (µCT). Body mass‐normalized peak isometric‐torque was 18% less in VML‐0.6 g mice compared with VML‐noTx mice (p = 0.030). There were no statistically significant differences of vibration intervention on contractile power or muscle oxygen consumption (p ≥ 0.191). Bone ultimate load, but not stiffness, was ~16% greater in tibias of VML‐1.0 g mice compared with those from VML‐noTx mice (p = 0.048). Cortical bone volume was ~12% greater in tibias of both vibration groups compared with VML‐noTx mice (p = 0.003). Importantly, cross‐section moment of inertia, the primary determinant of bone ultimate load, was 44% larger in tibias of VML‐0.6 g mice compared with VML‐noTx mice (p = 0.006). These changes indicate that following VML, bones are more responsive to the selected vibration training parameters than muscle. Vibration training represents a possible adjuvant intervention to address bone deficits following VML. [ABSTRACT FROM AUTHOR]

Background: Trabeculation is an integral component of cardiac ventricular morphogenesis and is dependent on the matrix metalloproteinase, ADAMTS1. A substrate of ADAMTS1 is the proteoglycan versican which is expressed in the developing ventricle and which has been implicated in trabeculation. Fibulin-1 is a versican and ADAMTS1-binding extracellular matrix protein required for ventricular morphogenesis. Here we investigated the involvement of fibulin-1 in ADAMTS1-mediated cleavage of versican in vitro, and the involvement of fibulin-1 in versican cleavage in ventricular morphogenesis. Results: We show that fibulin-1 is a cofactor for ADAMTS1-dependent in vitro cleavage of versican V1, yielding a 70-kDa amino-terminal fragment. Furthermore, fibulin-1-deficiency in mice was found to cause a significant reduction (>90%) in ventricular levels of the 70-kDa versican V1 cleavage product and a 2-fold increase in trabecular cardiomyocyte proliferation. Decreased versican V1 cleavage and augmented trabecular cardiomyocyte proliferation in fibulin-1 null hearts is accompanied by increased ventricular activation of ErbB2 and Erk1/2. By contrast, versican deficiency was found to lead to decreased cardiomyocyte proliferation and reduced ventricular trabeculation. Conclusion: We conclude that fibulin-1 regulates versican-dependent events in ventricular morphogenesis by promoting ADAMTS1 cleavage of versican leading to suppression of trabecular cardiomyocyte proliferation mediated by the ErbB2-Map kinase pathway. Developmental Dynamics 241:303-314, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of obesity has dramatically increased worldwide. Obesity has been shown to exacerbate the progression of periodontal disease. Studies suggest a sex difference in periodontitis, whereby males are more sensitive to periodontal inflammation compared to females. Aim: In the current study, it was hypothesized that obesity drives periodontal inflammation and bone loss in both sexes. Methodology: Utilizing leptin receptor mutant (SS LepR mutant) rats as a genetic model of obesity, 11-12-week-old male and female lean Dahl salt-sensitive (SS) rats and obese SS LepR mutant rats were used to investigate sex differences in obesity-induced periodontal inflammation. Results: Body weight, insulin, hemoglobin A1c and cholesterol levels were significantly elevated in the obese SS LepR mutant strain vs. the lean SS strain within the same sex. Sex differences in body weight and plasma hemoglobin A1c were only observed in obese SS LepR mutant rats, with males having significantly greater body weight and hemoglobin A1c vs. females. Plasma thiobarbituric acid reactive substances (TBARs) and monocyte chemoattractant protein-1 (MCP-1), markers of systemic oxidative stress and inflammation, respectively, were significantly elevated in obese SS LepR mutant rats vs. lean SS rats, with no sex differences in these parameters in either rat strains. Although micro-CT analyses of the maxillary first molar alveolar bone from obese SS LepR mutant rats revealed no evidence of bone loss and/or sex differences, immuno-histochemical analysis revealed significant elevations in periodontal IL-6 and decreases in IL-10 in obese SS LepR mutant rats vs. lean SS rats, with no apparent sex differences in these parameters. Conclusions: Obesity increases systemic and periodontal inflammation, without evidence of bone loss or apparent sex differences in SS LepR mutant rats.