A Cross-Species Analysis of a Mouse Model of Breast Cancer-Specific Osteolysis and Human Bone Metastases Using Gene Expression Profiling

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone. <it>In vivo </it>models that mimic the breast cancer-specific osteolytic bone microenvironment are limited. Previously, we developed a mouse model of tumor-bone interaction in which three mouse breast cancer cell lines were implanted onto the calvaria. Analysis of tumors from this model revealed that they exhibited strong bone resorption, induction of osteoclasts and intracranial penetration at the tumor bone (TB)-interface.</p> <p>Methods</p> <p>In this study, we identified and used a TB microenvironment-specific gene expression signature from this model to extend our understanding of the metastatic bone microenvironment in human disease and to predict potential therapeutic targets.</p> <p>Results</p> <p>We identified a TB signature consisting of 934 genes that were commonly (among our 3 cell lines) and specifically (as compared to tumor-alone area within the bone microenvironment) up- and down-regulated >2-fold at the TB interface in our mouse osteolytic model. By comparing the TB signature with gene expression profiles from human breast metastases and an <it>in vitro </it>osteoclast model, we demonstrate that our model mimics both the human breast cancer bone microenvironment and osteoclastogenesis. Furthermore, we observed enrichment in various signaling pathways specific to the TB interface; that is, TGF-β and myeloid self-renewal pathways were activated and the Wnt pathway was inactivated. Lastly, we used the TB-signature to predict cyclopenthiazide as a potential inhibitor of the TB interface.</p> <p>Conclusion</p> <p>Our mouse breast cancer model morphologically and genetically resembles the osteoclastic bone microenvironment observed in human disease. Characterization of the gene expression signature specific to the TB interface in our model revealed signaling mechanisms operative in human breast cancer metastases and predicted a therapeutic inhibitor of cancer-mediated osteolysis.</p

Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies

Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm2) between diabetic and non-diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross-sectional, cohort or case–control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA1C were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM

Assessment of the bone quality of black male athletes using calcaneal ultrasound: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Lifestyle, genetics and environmental factors are established determinants of bone density. We aimed to describe the bone characteristics of competitive top-ranked Nigerian male athletes using calcaneal ultrasound and to assess whether intensive training promotes higher bone density in an environment with reportedly low calcium intake; to compare the bone characteristics of footballers with runners and other sportsmen; and to assess the correlation of stiffness index (SI) with activity level, since energy expenditure correlates with length of training and by extension, magnitude of skeletal loading.</p> <p>Methods</p> <p>We recruited 102 male athletes: these included football (n = 68), running (n = 15), handball (n = 7), taekwando (n = 6), cycling (n = 2), judo (1), badminton (1) and high jump (1). Anthropometric data were first recorded on a structured form and energy expenditure was indirectly estimated with a validated questionnaire. Bone density was assessed using the Lunar Achilles+ calcaneal ultrasonometer.</p> <p>Results</p> <p>The mean age of athletes was 25 ± 6 years. The means of BMI and energy expenditure were 21.9 ± 2.0 kg/m²and 35.0 ± 13.7 kcal/kg/day, respectively. Footballers were younger (p < 0.001) and heavier (p < 0.001) than runners. Football was a significant determinant of BUA independent of age, BMI and energy expenditure (p = 0.001). Football was also a significant determinant of SOS independent of age, height, weight and BMI (p < 0.001). The mean SI was 127 ± 16 and the median T-score was 0.82 (-1.88, 3.35). The mean SI of footballers (130 ± 15), runners (130 ± 12) and other sportsmen (115 ± 18) differed significantly (p = 0.001). Multivariate analyses revealed that football (p < 0.001) and running (p < 0.001) were significant determinants of SI independent of age and BMI. Footballers when compared with other sportsmen had a higher mean SI independent of age and BMI (p < 0.001). Age was not correlated with SI. The median T-score of footballers, 0.94 (-1.0, 3.35) was higher than that of other sportsmen.</p> <p>Conclusion</p> <p>Repetitive skeletal loading at the heel has the potential to improve bone density in black male athletes. The magnitude of increase may be higher in medium impact sports such as soccer and running compared with low or non-impact sports such as judo or taekwando, and is independent of age and BMI. However, future longitudinal data will be required to support our observations.</p