Central Depletion of Brain-Derived Neurotrophic Factor in Mice Results in High Bone Mass and Metabolic Phenotype

Authors

Shanil S. Juma, Zahra Ezzat-Zadeh, Dania A. Khalil, Shirin Hooshmand, Mohammed Akhter, Bahram H. Arjmandi

Abstract

Brain-derived neurotrophic factor (BDNF) plays important roles in neuronal differentiation/survival, the regulation of food intake, and the pathobiology of obesity and type 2 diabetes mellitus. BDNF and its receptor are expressed in osteoblasts and chondrocyte. BDNF in vitro has a positive effect on bone; whether central BDNF affects bone mass in vivo is not known. We therefore examined bone mass and energy use in brain-targeted BDNF conditional knockout mice (Bdnf2lox/2lox/93). The deletion of BDNF in the brain led to a metabolic phenotype characterized by hyperphagia, obesity, and increased abdominal white adipose tissue. Central BDNF deletion produces a marked skeletal phenotype characterized by increased femur length, elevated whole bone mineral density, and bone mineral content. The skeletal changes are developmentally regulated and appear concurrently with the metabolic phenotype, suggesting that the metabolic and skeletal actions of BDNF are linked. The increased bone development is evident in both the cortical and trabecular regions. Compared with control, Bdnf2lox/2lox/93 mice show greater trabecular bone volume (+50% for distal femur, P < 0.001; +35% for vertebral body, P < 0.001) and midfemoral cortical thickness (+11 to 17%, P < 0.05), measured at 3 and 6 months of age. The skeletal and metabolic phenotypes were gender dependent, with female being more affected than male mice. However, uncoupling protein-1 expression in brown fat, a marker of sympathetic tone, was not different between genotypes. We show that deletion of central BDNF expression in mice results in increased bone mass and white adipose tissue, with no significant changes in sympathetic signaling or peripheral serotonin, associated with hyperphagia, obesity, and leptin resistance.

Link to Article

http://dx.doi.org/10.1210/en.2012-1378

Hyperglycemia and xerostomia are key determinants of tooth decay in type 1 diabetic mice

Authors

Chih-Ko Yeh, Stephen E Harris, Sumathy Mohan, Diane Horn, Roberto Fajardo, Yong-Hee Patricia Chun, James Jorgensen, Mary MacDougall and Sherry Abboud-Werner

Abstract

Insulin-dependent type 1 diabetes mellitus (DM) and oral diseases are closely interrelated. Poor metabolic control in diabetics is associated with a high risk of gingivitis, periodontitis and tooth loss. Salivary flow declines in diabetics and patients suffer from xerostomia. Reduced saliva predisposes to enamel hypomineralization and caries formation; however, the mechanisms that initiate and lead to progression of tooth decay and periodontitis in type 1 DM have not been explored. To address this issue, we analyzed tooth morphology in Akita −/− mice that harbor a point mutation in the Ins2 insulin gene, which leads to progressive hyperglycemia. Mandibles from Akita −/− and wild-type littermates were analyzed by microCT, scanning EM and histology; teeth were examined for amelogenin (Amel) and ameloblastin (Ambn) expression. Mice were injected with pilocarpine to assess saliva production. As hyperglycemia may alter pulp repair, the effect of high glucose levels on the proliferation/differentiation of cultured MD10-F2 pulp cells was also analyzed. Results showed that Akita −/− mice at 6 weeks of age showed chalky white incisors that correlated with marked hyperglycemia and impaired saliva production. MicroCT of Akita −/− teeth revealed excessive enamel wearing and hypomineralization; immunostaining for Amel and Ambn was decreased. A striking feature was invasion of dentinal tubules with Streptococcus mitis and microabcesses that originated in the coronal pulp and progressed to pulp necrosis and periapical periodontitis. High levels of glucose also inhibited MD10-F2 cell proliferation and differentiation. Our findings provide the first evidence that hyperglycemia in combination with reduced saliva in a model of type1 DM leads to decreased enamel mineralization/matrix proteins and predisposes to excessive wearing and decay. Importantly, hyperglycemia adversely affects enamel matrix proteins and pulp repair. Early detection and treatment of hyperglycemia and hyposalivation may provide a useful strategy for preventing the dental complications of diabetes and promoting oral health in this population.

Link to Article

http://dx.doi.org/10.1038/labinvest.2012.60

Trabecular bone histomorphometry in humans with type 1 diabetes Mellitus

Authors

Laura A.G. Armas, Mohammed P. Akhter, Andjela Drincic, Robert R. Recker

Abstract

Patients with Type 1 Diabetes Mellitus (DM) have markedly increased risk of fracture, but little is known about abnormalities in bone micro-architecture or remodeling properties that might give insight into the pathogenesis of skeletal fragility in these patients. We report here a case–control study comparing bone histomorphometric and micro-CT results from iliac biopsies in 18 otherwise healthy subjects with Type 1 Diabetes Mellitus with those from healthy age- and sex- matched non-diabetic control subjects. Five of the diabetics had histories of low-trauma fracture. Transilial bone biopsies were obtained after tetracycline labeling. The biopsy specimens were fixed, embedded, and scanned using a desktop μCT at 16 micron resolution. They were then sectioned and quantitative histomorphometry was performed as previously described by Recker et al. 1988.[1] Two sections, > 250 μm apart, were read from the central part of each biopsy. Overall there were no significant differences between diabetics and controls in histomorphometric or micro-CT measurements. However, fracturing diabetics had structural and dynamic trends different from nonfracturing diabetics by both methods of analysis. In conclusion, Type 1 Diabetes Mellitus does not result in abnormalities in bone histomorphometric or micro-CT variables in the absence of manifest complications from the diabetes. However, diabetics suffering fractures may have defects in their skeletal microarchitecture that may underlie the presence of excess skeletal fragility.

Link to Article

http://dx.doi.org/10.1016/j.bone.2011.09.055

Diabetes mellitus negatively affects peri-implant bone formation in the diabetic domestic pig

Authors

Cornelius von Wilmowsky, Philipp Stockmann, Igor Harsch, Kerstin Amann, Philipp Metzler, Rainer Lutz, Tobias Moest, Friedrich Wilhelm Neukam, Karl Andreas Schlegel

Abstract

Diabetes mellitus is classified as a relative contraindication for implant treatment, and higher failure rates have been seen in diabetic patients. The aim of the present study was to investigate the effect of diabetes on peri-implant bone formation in an animal model of human bone repair. Diabetes was induced by an intravenous application of streptozotocin (90 mg/kg) in 15 domestic pigs. Implants were placed after significant histopathological changes in the hard and soft tissues were verified. The bone–implant contact (BIC), peri-implant bone mineral density (BMD), and expression of collagen type-I and osteocalcin proteins were qualitatively evaluated 4 and 12 weeks after implantation. Fifteen animals served as healthy controls. Diabetes caused pathological changes in the soft and hard tissues. The BIC and BMD were significantly reduced in the diabetic group after 4 and 12 weeks. Collagen type-I was increased in the diabetic group at both time points, whereas osteocalcin was reduced in the diabetic group. Poorly controlled diabetes negatively affects peri-implant bone formation and bone mineralization. These findings have to be taken into consideration for diabetic patients with an indication for implant therapy.

Link to Article

http://dx.doi.org/10.1111/j.1600-051X.2011.01746.x

Establishment of a streptozotocin-induced diabetic domestic pig model and a systematic evaluation of pathological changes in the hard and soft tissue over a 12-month period

Authors

Cornelius Von Wilmowsky, Philipp Stockmann, Philipp Metzler, Igor Alexander Harsch, Kerstin Amann, Karl Andreas Schlegel

Abstract

The number of diabetic patients in need of medical treatment is growing steadily. Therefore, a diabetic animal model with high degree of similarities with humans, which is suitable for the systematic evaluation of biomaterials and medical devices, is needed. Twenty domestic pigs were used for the study. Fifteen received Streptozotocin (STZ) to induce diabetes mellitus. Internal parameters were measured and bone as well as soft tissues biopsies were taken after 0, 6 and 12 months and evaluated qualitatively and quantitatively by means of scanning electronic microscopy, light microscopy and microradiography. The results of the clinical internal parameters, determined by the American Diabetes Association for the definition of diabetes mellitus could be fulfilled. Pathological changes of the skin vasculatures were already visible after 6 months with a significant wall thickening in the diabetic group. The bone mineralization was lower in the diabetic group after 6 months and with a significant difference after 12 months. From the present results, it can be concluded that a STZ dosage of 90 mg/kg body weight in the domestic pig is suitable for the induction of an apparent diabetes, leading to histolopathological changes in the hard and soft tissues already after 6 months. The high degree of similarities with humans makes it an interesting diabetic animal model for biomaterial research in a compromised animal model. To cite this article: von Wilmowsky C, Stockmann P, Metzler P, Harsch IA, Amann K, Schlegel KA. Establishment of a streptozotocin-induced diabetic domestic pig model and a systematic evaluation of pathological changes in the hard and soft tissue over a 12-month period.

Link to Article

http://dx.doi.org/10.1111/j.1600-0501.2010.01914.x