Back pain is a leading cause of global disability that can arise from vertebral fracture and osteoporosis. Although poor general health and obesity are among the strongest risk factors for back pain, there is remarkably little known about how diet influences spinal diseases. Advanced glycation end-products (AGEs) are implicated in increased fracture risk, yet no studies investigated how dietary AGEs affect spinal health. We tested the hypothesis that high dietary AGE ingestion will diminish vertebral structure and function in a sex- and age-dependent manner. Female and male mice were fed low-AGE (L-AGE) or high-AGE (H-AGE) isocaloric diets for 6 and 18 months and multiple measurements of bone structure and function were taken. AGE levels in serum and cortical vertebrae were increased only for 6-month-old H-AGE female mice while blood glucose and body weight remained normal for all animals. When fed an H-AGE diet, 6-month-old female mice had inferior vertebral trabecular structure with decreased bone mineral density (BMD) and bone volume fraction. Biomechanical testing and analytical modeling further showed functional deterioration in 6-month-old H-AGE females with reduced shear and compression moduli, and maximum load to failure. At 18 months, H-AGE mice of both sexes had significant but small decreases in cortical BMD and thickness, yet functional biomechanical behaviors were not distinguishable from other aging changes. We conclude that an H-AGE diet, without diabetic or overweight conditions, diminished vertebral microstructure, mechanical behaviors, and fracture resistance in young female mice in a manner suggesting accelerated bone aging. © 2017 American Society for Bone and Mineral Research.

Spontaneous preterm birth (sPTB) is a leading cause of maternal and neonatal morbidity and mortality, yet its prevention and early risk stratification are limited. Previous investigations have suggested that vaginal microbes and metabolites may be implicated in sPTB. Here we performed untargeted metabolomics on 232 second-trimester vaginal samples, 80 from pregnancies ending preterm. We find multiple associations between vaginal metabolites and subsequent preterm birth, and propose that several of these metabolites, including diethanolamine and ethyl glucoside, are exogenous. We observe associations between the metabolome and microbiome profiles previously obtained using 16S ribosomal RNA amplicon sequencing, including correlations between bacteria considered suboptimal, such as Gardnerella vaginalis, and metabolites enriched in term pregnancies, such as tyramine. We investigate these associations using metabolic models. We use machine learning models to predict sPTB risk from metabolite levels, weeks to months before birth, with good accuracy (area under receiver operating characteristic curve of 0.78). These models, which we validate using two external cohorts, are more accurate than microbiome-based and maternal covariates-based models (area under receiver operating characteristic curve of 0.55–0.59). Our results demonstrate the potential of vaginal metabolites as early biomarkers of sPTB and highlight exogenous exposures as potential risk factors for prematurity.

Ectopic calcifications in intervertebral discs (IVDs) are known characteristics of IVD degeneration that are not commonly reported but may be implicated in structural failure and dysfunctional IVD cell metabolic responses. This study investigated the novel hypothesis that ectopic calcifications in the IVD are associated with advanced glycation end products (AGEs) via hypertrophy and osteogenic differentiation. Histological analyses of human IVDs from several degeneration stages revealed areas of ectopic calcification within the nucleus pulposus and at the cartilage endplate. These ectopic calcifications were associated with cells positive for the AGE methylglyoxal-hydroimidazolone-1 (MG-H1). MG-H1 was also co-localised with Collagen 10 (COL10) and Osteopontin (OPN) suggesting osteogenic differentiation. Bovine nucleus pulposus and cartilaginous endplate cells in cell culture demonstrated that 200 μg/mL AGEs in low-glucose media increased ectopic calcifications after 4 d in culture and significantly increased COL10 and OPN expression. The receptor for AGE (RAGE) was involved in this differentiation process since its inhibition reduced COL10 and OPN expression. We conclude that AGE accumulation is associated with endochondral ossification in IVDs and likely acts via the AGE/RAGE axis to induce hypertrophy and osteogenic differentiation in IVD cells. We postulate that this ectopic calcification may play an important role in accelerated IVD degeneration including the initiation of structural defects. Since orally administered AGE and RAGE inhibitors are available, future investigations on AGE/RAGE and endochondral ossification may be a promising direction for developing non-invasive treatment against progression of IVD degeneration.

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Spontaneous preterm birth (sPTB) is a leading cause of maternal and neonatal morbidity and mortality, yet both its prevention and early risk stratification are limited. The vaginal microbiome has been associated with PTB risk, possibly via metabolic or other interactions with its host. Here, we performed untargeted metabolomics on 232 vaginal samples, in which we have previously profiled the microbiota using 16S rRNA gene sequencing. Samples were collected at 20-24 weeks of gestation from women with singleton pregnancies, of which 80 delivered spontaneously before 37 weeks of gestation. We find that the vaginal metabolome correlates with the microbiome and separates into six clusters, three of which are associated with spontaneous preterm birth (sPTB) in Black women. Furthermore, while we identify five metabolites that associate with sPTB, another five associate with sPTB only when stratifying by race. We identify multiple microbial correlations with metabolites associated with sPTB, including intriguing correlations between vaginal bacteria that are considered sub-optimal and metabolites that were enriched in women who delivered at term. We propose that several sPTB-associated metabolites may be exogenous, and investigate another using metabolic models. Notably, we use machine learning models to predict sPTB risk using metabolite levels, weeks to months in advance, with high accuracy. We show that these predictions are more accurate than microbiome-based and maternal covariates-based models. Altogether, our results demonstrate the potential of vaginal metabolites as early biomarkers of sPTB and highlight exogenous exposures as potential risk factors for prematurity.

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Introduction Accumulation of advanced glycation end products (AGE) are commonly associated with diabetic complications, including increased painful intervertebral disc pathologies, osteoporosis, and bone fracture risk. Exogenous AGEs develop by processing food at high temperatures and can accumulate in bone where they crosslink collagen. A clinical study reported association of increased serum AGE levels with vertebral fracture risk in women but not in men, highlighting gender effects. The purpose of this study was to investigate the sex-dependent effects of exogenous AGEs on vertebral bone quantity, quality, and mechanical behavior. Material and Methods C57BL/6 mice (female, n = 8/group; male, n = 4/group) were pair-fed isocaloric diets containing low AGE amounts (LAGE, 7.6 μg/mg chow) or high AGE amounts (HAGE, 40.9 μg/mg chow) for 6 months; after euthanasia, blood glucose and serum AGEs were analyzed. Lumbar spines were μCT-scanned (resolution=4.9μm; SkyScan 1172, Bruker Corp., Belgium). Hydroxyapatite phantoms were similarly scanned for density calibration. Cortical bone analysis included tissue mineral density (TMD), BMD, cross sectional thickness (Ct.Th), bone surface are (BSA) and porosity. Trabecular bone analysis included trabecular thickness, separation (Tb.Sp), number (Tb.Nm), TMD, BMD, BVF, bone surface to volume ratio (BS/BV), Structure Model Index (SMI) and fabric anisotropy. A validated analytical model was used to calculate trabecular bone anisotropic compressive and shear moduli. Male/female and HAGE/LAGE differences were analyzed via Student's t-tests (p < 0.05). All experiments were approved by the Institutional Animal Care and Use Committee. Results Serum AGE levels were significantly increased in female HAGE mice compared with LAGE mice (p < 0.01). No differences were observed between blood glucose levels among groups. Dietary comparisons indicated that female trabecular BS/BV and porosity were significantly increased by HAGE-diet whereas trabecular BMD, compressive and shear moduli, and cortical BMD were decreased. In males dietary comparisons revealed only a significant increase in trabecular porosity. Male cortical bone remained unchanged. Sex comparisons within LAGE-diet group revealed that female trabecular bone had significantly reduced Tb.Nm, BMD, degree of anisotropy, compressive and shear moduli, and significantly increased Tb.Sp, porosity, and SMI compared with LAGE males. LAGE females also had significantly decreased cortical BSA and significantly increased Ct.Th compared with LAGE males. Sex comparisons of female versus male HAGE-diet groups revealed no significant differences. Conclusion Results indicated more pronounced detrimental effects on cortical and trabecular bone in females on HAGE-diet than in males. These sex-dependent effects suggest that AGEs effects on vertebral bone may be hormonally mediated. This work showed for the first time significant alterations to the elastic compressive and shear properties of vertebra following variations in dietary AGE levels. Cha...