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The proto-oncogene function of Mdm2 in bone.
Olivos DJ, Perrien DS, Hooker A, Cheng YH, Fuchs RK, Hong JM, Bruzzaniti A, Chun K, Eischen CM, Kacena MA, Mayo LD
(2018) J Cell Biochem 119: 8830-8840
MeSH Terms: Analysis of Variance, Animals, Bone Density, Bone Remodeling, Calcification, Physiologic, Cancellous Bone, Cell Line, Tumor, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Osteoblasts, Osteoclasts, Osteogenesis, Osteosarcoma, Proto-Oncogene Proteins c-mdm2, Proto-Oncogenes
Show Abstract · Added April 1, 2019
Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2 ) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblast-specific Mdm2 overexpressing (Mdm2 ) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected age-related bone loss in mice, providing a role for the proto-oncogenic activity of Mdm2 in bone health of adult animals.
© 2018 Wiley Periodicals, Inc.
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19 MeSH Terms
The Role of Matrix Composition in the Mechanical Behavior of Bone.
Unal M, Creecy A, Nyman JS
(2018) Curr Osteoporos Rep 16: 205-215
MeSH Terms: Biomechanical Phenomena, Bone Density, Bone Matrix, Bone and Bones, Cancellous Bone, Collagen Type I, Fractures, Bone, Glycation End Products, Advanced, Humans, Minerals, Protein Processing, Post-Translational, Tropocollagen, Water
Show Abstract · Added April 9, 2018
PURPOSE OF REVIEW - While thinning of the cortices or trabeculae weakens bone, age-related changes in matrix composition also lower fracture resistance. This review summarizes how the organic matrix, mineral phase, and water compartments influence the mechanical behavior of bone, thereby identifying characteristics important to fracture risk.
RECENT FINDINGS - In the synthesis of the organic matrix, tropocollagen experiences various post-translational modifications that facilitate a highly organized fibril of collagen I with a preferred orientation giving bone extensibility and several toughening mechanisms. Being a ceramic, mineral is brittle but increases the strength of bone as its content within the organic matrix increases. With time, hydroxyapatite-like crystals experience carbonate substitutions, the consequence of which remains to be understood. Water participates in hydrogen bonding with organic matrix and in electrostatic attractions with mineral phase, thereby providing stability to collagen-mineral interface and ductility to bone. Clinical tools sensitive to age- and disease-related changes in matrix composition that the affect mechanical behavior of bone could potentially improve fracture risk assessment.
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13 MeSH Terms
Low bone toughness in the TallyHO model of juvenile type 2 diabetes does not worsen with age.
Creecy A, Uppuganti S, Unal M, Clay Bunn R, Voziyan P, Nyman JS
(2018) Bone 110: 204-214
MeSH Terms: Aging, Animals, Arginine, Bone Density, Chromatography, High Pressure Liquid, Diabetes Mellitus, Type 2, Femur, Fractures, Bone, Lysine, Male, Mice, Spectrum Analysis, Raman, X-Ray Microtomography
Show Abstract · Added February 19, 2018
Fracture risk increases as type 2 diabetes (T2D) progresses. With the rising incidence of T2D, in particular early-onset T2D, a representative pre-clinical model is needed to study mechanisms for treating or preventing diabetic bone disease. Towards that goal, we hypothesized that fracture resistance of bone from diabetic TallyHO mice decreases as the duration of diabetes increases. Femurs and lumbar vertebrae were harvested from male, TallyHO mice and male, non-diabetic SWR/J mice at 16weeks (n≥12 per strain) and 34weeks (n≥13 per strain) of age. As is characteristic of this model of juvenile T2D, the TallyHO mice were obese and hyperglycemic at an early age (5weeks and 10weeks of age, respectively). The femur mid-shaft of TallyHO mice had higher tissue mineral density and larger cortical area, as determined by micro-computed tomography, compared to the femur mid-shaft of SWR/J mice, irrespective of age. As such, the diabetic rodent bone was structurally stronger than the non-diabetic rodent bone, but the higher peak force endured by the diaphysis during three-point (3pt) bending was not independent of the difference in body weight. Upon accounting for the structure of the femur diaphysis, the estimated toughness at 16weeks and 34weeks was lower for the diabetic mice than for non-diabetic controls, but neither toughness nor estimated material strength and resistance to crack growth (3pt bending of contralateral notched femur) decreased as the duration of hyperglycemia increased. With respect to trabecular bone, there were no differences in the compressive strength of the L6 vertebral strength between diabetic and non-diabetic mice at both ages despite a lower trabecular bone volume for the TallyHO than for the SWR/J mice at 34weeks. Amide I sub-peak ratios as determined by Raman Spectroscopy analysis of the femur diaphysis suggested a difference in collagen structure between diabetic and non-diabetic mice, although there was not a significant difference in matrix pentosidine between the groups. Overall, the fracture resistance of bone in the TallyHO model of T2D did not progressively decrease with increasing duration of hyperglycemia. However, given the variability in hyperglycemia in this model, there were correlations between blood glucose levels and certain structural properties including peak force.
Copyright © 2018 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Adipose tissue depot volume relationships with spinal trabecular bone mineral density in African Americans with diabetes.
Chan GC, Divers J, Russell GB, Langefeld CD, Wagenknecht LE, Xu J, Smith SC, Bowden DW, Register TC, Carr JJ, Lenchik L, Freedman BI
(2018) PLoS One 13: e0191674
MeSH Terms: Adipose Tissue, Adult, African Americans, Bone Density, Diabetes Mellitus, Type 2, Female, Humans, Longitudinal Studies, Male, Middle Aged, Spine
Show Abstract · Added January 10, 2020
Changes in select adipose tissue volumes may differentially impact bone mineral density. This study was performed to assess cross-sectional and longitudinal relationships between computed tomography-determined visceral (VAT), subcutaneous (SAT), inter-muscular (IMAT), and pericardial adipose tissue (PAT) volumes with respective changes in thoracic vertebral and lumbar vertebral volumetric trabecular bone mineral density (vBMD) in African Americans with type 2 diabetes. Generalized linear models were fitted to test relationships between baseline and change in adipose volumes with change in vBMD in 300 African American-Diabetes Heart Study participants; adjustment was performed for age, sex, diabetes duration, study interval, smoking, hypertension, BMI, kidney function, and medications. Participants were 50% female with mean ± SD age 55.1±9.0 years, diabetes duration 10.2±7.2 years, and BMI 34.7±7.7 kg/m2. Over 5.3 ± 1.4 years, mean vBMD decreased in thoracic/lumbar spine, while mean adipose tissue volumes increased in SAT, IMAT, and PAT, but not VAT depots. In fully-adjusted models, changes in lumbar and thoracic vBMD were positively associated with change in SAT (β[SE] 0.045[0.011], p<0.0001; 0.40[0.013], p = 0.002, respectively). Change in thoracic vBMD was positively associated with change in IMAT (p = 0.029) and VAT (p = 0.016); and change in lumbar vBMD positively associated with baseline IMAT (p<0.0001). In contrast, vBMD was not associated with change in PAT. After adjusting for BMI, baseline and change in volumes of select adipose depots were associated with increases in thoracic and lumbar trabecular vBMD in African Americans. Effects of adiposity on trabecular bone appear to be site-specific and related to factors beyond mechanical load.
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Bone Mineral Density of the Radius Predicts All-Cause Mortality in Patients With Type 2 Diabetes: Diabetes Heart Study.
Lenchik L, Register TC, Hsu FC, Xu J, Smith SC, Carr JJ, Freedman BI, Bowden DW
(2018) J Clin Densitom 21: 347-354
MeSH Terms: Absorptiometry, Photon, Aged, Bone Density, Diabetes Mellitus, Type 2, Female, Femur Neck, Humans, Longitudinal Studies, Lumbar Vertebrae, Male, Middle Aged, Mortality, Radius, Sex Factors, Thoracic Vertebrae, Tomography, X-Ray Computed
Show Abstract · Added January 10, 2020
This study aimed to determine the association between areal and volumetric bone mineral density (BMD) with all-cause mortality in patients with type 2 diabetes (T2D). Associations between BMD and all-cause mortality were examined in 576 women and 517 men with T2D in the Diabetes Heart Study. Volumetric BMD in the thoracic and lumbar spine was measured with quantitative computed tomography. Areal BMD (aBMD) in the lumbar spine, total hip, femoral neck, ultradistal radius, mid radius, and whole body was measured using dual X-ray absorptiometry. Association of BMD with all-cause mortality was determined using sequential models, stratified by sex: (1) unadjusted; (2) adjusted for age, race, smoking, alcohol, estrogen use; (3) model 2 plus history of cardiovascular disease, hypertension, and coronary artery calcification; (4) model 3 plus lean mass; and (5) model 3 plus fat mass. At baseline, mean age was 61.2 years for women and 62.7 years for men. At mean 11.0 ± 3.7 years' follow-up, 221 (36.4%) women and 238 (43.6%) men were deceased. In women, BMD at all skeletal sites (except spine aBMD and whole body aBMD) was inversely associated with all-cause mortality in the unadjusted model. These associations remained significant in the mid radius (hazard ratio per standard deviation  = 0.79; p = 0.0057) and distal radius (hazard ratio per standard deviation  = 0.76; p = 0.0056) after adjusting for all covariates, including lean mass. In men, volumetric BMD measurements but not aBMD were inversely associated with mortality and only in the unadjusted model. In this longitudinal study, lower baseline aBMD in the radius was associated with increased all-cause mortality in women with T2D, but not men, independent of other risk factors for death.
Copyright © 2017 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.
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Daily parathyroid hormone administration enhances bone turnover and preserves bone structure after severe immobilization-induced bone loss.
Harlow L, Sahbani K, Nyman JS, Cardozo CP, Bauman WA, Tawfeek HA
(2017) Physiol Rep 5:
MeSH Terms: Animals, Bone Density, Bone Remodeling, Cancellous Bone, Cortical Bone, Female, Mice, Mice, Inbred C57BL, Osteoporosis, Parathyroid Hormone, Spinal Cord Injuries
Show Abstract · Added October 1, 2017
Immobilization, as a result of motor-complete spinal cord injury (SCI), is associated with severe osteoporosis. Whether parathyroid hormone (PTH) administration would reduce bone loss after SCI remains unclear. Thus, female mice underwent sham or surgery to produce complete spinal cord transection. PTH (80 g/kg) or vehicle was injected subcutaneously (SC) daily starting on the day of surgery and continued for 35 days. Isolated tibias and femurs were examined by microcomputed tomography scanning (micro-CT) and histology and serum markers of bone turnover were measured. Micro-CT analysis of tibial metaphysis revealed that the SCI-vehicle animals exhibited 49% reduction in fractional trabecular bone volume and 18% in trabecular thickness compared to sham-vehicle controls. SCI-vehicle animals also had 15% lower femoral cortical thickness and 16% higher cortical porosity than sham-vehicle counterparts. Interestingly, PTH administration to SCI animals restored 78% of bone volume, increased connectivity to 366%, and lowered structure model index by 10% compared to sham-vehicle animals. PTH further favorably attenuated femoral cortical bone loss to 5% and prevented the SCI-associated cortical porosity. Histomorphometry evaluation of femurs of SCI-vehicle animals demonstrated a marked 49% and 38% decline in osteoblast and osteoclast number, respectively, and 35% reduction in bone formation rate. In contrast, SCI-PTH animals showed preserved osteoblast and osteoclast numbers and enhanced bone formation rate. Furthermore, SCI-PTH animals had higher levels of bone formation and resorption markers than either SCI- or sham-vehicle groups. Collectively, these findings suggest that intermittent PTH receptor activation is an effective therapeutic strategy to preserve bone integrity after severe immobilization.
© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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11 MeSH Terms
Enhanced Identification of Potential Pleiotropic Genetic Variants for Bone Mineral Density and Breast Cancer.
Peng C, Lou HL, Liu F, Shen J, Lin X, Zeng CP, Long JR, Su KJ, Zhang L, Greenbaum J, Deng WF, Li YM, Deng HW
(2017) Calcif Tissue Int 101: 489-500
MeSH Terms: Bone Density, Breast Neoplasms, Female, Genetic Pleiotropy, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide
Show Abstract · Added April 10, 2018
Epidemiological and clinical evidences have shown that bone mineral density (BMD) has a close relationship with breast cancer (BC). They might potentially have a shared genetic basis. By incorporating information about these pleiotropic effects, we may be able to explore more of the traits' total heritability. We applied a recently developed conditional false discovery rate (cFDR) method to the summary statistics from two independent GWASs to identify the potential pleiotropic genetic variants for BMD and BC. By jointly analyzing two large independent GWASs of BMD and BC, we found strong pleiotropic enrichment between them and identified 102 single-nucleotide polymorphisms (SNPs) in BMD and 192 SNPs in BC with cFDR < 0.05, including 230 SNPs that might have been overlooked by the standard GWAS analysis. cFDR-significant genes were enriched in GO terms and KEGG pathways which were crucial to bone metabolism and/or BC pathology (adjP < 0.05). Some cFDR-significant genes were partially validated in the gene expressional validation assay. Strong interactions were found between proteins produced by cFDR-significant genes in the context of biological mechanism of bone metabolism and/or BC etiology. Totally, we identified 7 pleiotropic SNPs that were associated with both BMD and BC (conjunction cFDR < 0.05); CCDC170, ESR1, RANKL, CPED1, and MEOX1 might play important roles in the pleiotropy of BMD and BC. Our study highlighted the significant pleiotropy between BMD and BC and shed novel insight into trait-specific as well as the potentially shared genetic architecture for both BMD and BC.
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The Relationship of Bone Mineral Density in Men with Chronic Obstructive Pulmonary Disease Classified According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Combined Chronic Obstructive Pulmonary Disease (COPD) Assessment System.
Sakurai-Iesato Y, Kawata N, Tada Y, Iesato K, Matsuura Y, Yahaba M, Suzuki T, Ikari J, Yanagawa N, Kasahara Y, West J, Tatsumi K
(2017) Intern Med 56: 1781-1790
MeSH Terms: Absorptiometry, Photon, Aged, Asian Continental Ancestry Group, Bone Density, Cross-Sectional Studies, Humans, Male, Middle Aged, Osteoporosis, Pulmonary Disease, Chronic Obstructive, Surveys and Questionnaires
Show Abstract · Added April 2, 2019
Objective Osteoporosis, which is now recognized as a major comorbidity of chronic obstructive pulmonary disease (COPD), must be diagnosed by appropriate methods. The aims of this study were to clarify the relationships between bone mineral density (BMD) and COPD-related clinical variables and to explore the association of BMD with the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification in men. Methods We enrolled 50 Japanese men with clinically stable COPD who underwent dual-energy X-ray absorptiometry (DEXA), pulmonary function testing, and computerized tomography (CT) and who had completed a questionnaire (COPD assessment test [CAT]). We determined the association between the T-score and other tested parameters and compared the BMD of patients in each GOLD category. Results Twenty-three of the 50 patients (46.0%) were diagnosed with osteopenia, and 7 (14.0%) were diagnosed with osteoporosis. The BMD findings were significantly correlated with the CAT score, forced expiratory volume in 1 second percentage predicted (FEV% predicted), low attenuation volume percentage (LAV%), and percentage of cross-sectional area of small pulmonary vessels (%CSA) on CT images. Notably, the median T-score of the GOLD category D participants was significantly lower than that of the participants in each of the other categories (A [-0.98], B [-1.06], C [-1.05], and D [-2.19], p<0.05). Conclusion Reduced BMD was associated with airflow limitation, extent of radiographic findings, and a poor quality of life (QOL) in patients with COPD. The BMD of GOLD category D patients was the lowest of all of the patients evaluated, and category D patients may benefit from active intervention for osteoporosis.
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Applying Full Spectrum Analysis to a Raman Spectroscopic Assessment of Fracture Toughness of Human Cortical Bone.
Makowski AJ, Granke M, Ayala OD, Uppuganti S, Mahadevan-Jansen A, Nyman JS
(2017) Appl Spectrosc 71: 2385-2394
MeSH Terms: Adult, Aged, Aged, 80 and over, Bone Density, Collagen, Cortical Bone, Female, Fractures, Bone, Humans, Male, Middle Aged, Spectrum Analysis, Raman, Young Adult
Show Abstract · Added July 17, 2017
A decline in the inherent quality of bone tissue is a † Equal contributors contributor to the age-related increase in fracture risk. Although this is well-known, the important biochemical factors of bone quality have yet to be identified using Raman spectroscopy (RS), a nondestructive, inelastic light-scattering technique. To identify potential RS predictors of fracture risk, we applied principal component analysis (PCA) to 558 Raman spectra (370-1720 cm) of human cortical bone acquired from 62 female and male donors (nine spectra each) spanning adulthood (age range = 21-101 years). Spectra were analyzed prior to R-curve, nonlinear fracture mechanics that delineate crack initiation (K) from crack growth toughness (K). The traditional νphosphate peak per amide I peak (mineral-to-matrix ratio) weakly correlated with K (r = 0.341, p = 0.0067) and overall crack growth toughness (J-int: r = 0.331, p = 0.0086). Sub-peak ratios of the amide I band that are related to the secondary structure of type 1 collagen did not correlate with the fracture toughness properties. In the full spectrum analysis, one principal component (PC5) correlated with all of the mechanical properties (K: r = - 0.467, K: r = - 0.375, and J-int: r = - 0.428; p < 0.0067). More importantly, when known predictors of fracture toughness, namely age and/or volumetric bone mineral density (vBMD), were included in general linear models as covariates, several PCs helped explain 45.0% (PC5) to 48.5% (PC7), 31.4% (PC6), and 25.8% (PC7) of the variance in K, K, and J-int, respectively. Deriving spectral features from full spectrum analysis may improve the ability of RS, a clinically viable technology, to assess fracture risk.
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Bone Mineral Density and Progression of Subclinical Atherosclerosis in African-Americans With Type 2 Diabetes.
Wagenknecht LE, Divers J, Register TC, Russell GB, Bowden DW, Xu J, Langefeld CD, Lenchik L, Hruska KA, Carr JJ, Freedman BI
(2016) J Clin Endocrinol Metab 101: 4135-4141
MeSH Terms: Adipose Tissue, African Americans, Aortic Diseases, Atherosclerosis, Bone Density, Calcinosis, Carotid Artery Diseases, Comorbidity, Coronary Vessels, Diabetes Mellitus, Type 2, Disease Progression, Female, Humans, Male, Middle Aged, Plaque, Atherosclerotic
Show Abstract · Added September 29, 2016
CONTEXT - Relative to European Americans, calcified atherosclerotic plaque (CP) is less prevalent and severe in African-Americans (AAs).
OBJECTIVE - Predictors of progression of CP in the aorta, carotid, and coronary arteries were examined in AAs over a mean 5.3 ± 1.4-year interval.
DESIGN - This is the African American-Diabetes Heart Study.
SETTING - A type 2 diabetes (T2D)-affected cohort was included.
PARTICIPANTS - A total of 300 unrelated AAs with T2D; 50% female, mean age 55 ± 9 years, baseline hemoglobin A1c 8.1 ± 1.8% was included.
MAIN OUTCOME MEASURES - Glycemic control, renal parameters, vitamin D, and computed tomography-derived measures of adiposity, vascular CP, and volumetric bone mineral density (vBMD) in lumbar and thoracic vertebrae were obtained at baseline and follow-up.
RESULTS - CP increased in incidence and quantity/mass in all three vascular beds over the 5-year study (P < .0001). Lower baseline lumbar and thoracic vBMD were associated with progression of abdominal aorta CP (P < .008), but not progression of carotid or coronary artery CP. Lower baseline estimated glomerular filtration rate was associated with progression of carotid artery CP (P = .0004), and higher baseline pericardial adipose volume was associated with progression of coronary artery (P = .001) and aorta (P = .0006) CP independent of body mass index. There was a trend for an inverse relationship between change in thoracic vBMD and change in aortic CP (P = .05).
CONCLUSIONS - In this longitudinal study, lower baseline thoracic and lumbar vBMD and estimated glomerular filtration rate and higher pericardial adipose volumes were associated with increases in CP in AAs with T2D. Changes in these variables and baseline levels and/or changes in glycemic control, albuminuria, and vitamin D were not significantly associated with progression of CP.
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16 MeSH Terms