scholarly journals Age dependence of systemic bone loss and recovery following femur fracture in mice

2018 ◽  
Author(s):  
Armaun J. Emami ◽  
Chrisoula A. Toupadakis ◽  
Stephanie M. Telek ◽  
David P. Fyhrie ◽  
Clare E. Yellowley ◽  
...  
Keyword(s):  
Bone Loss ◽  
Fracture Risk ◽  
Trabecular Bone ◽  
Voluntary Movement ◽  
Whole Body ◽  
Middle Aged ◽  
Aged Mice ◽  
Future Fracture ◽  
Systemic Bone Loss ◽  
Young Mice

AbstractThe most reliable predictor of future fracture risk is a previous fracture of any kind. The etiology of this increased fracture risk is not fully known, but it is possible that fracture initiates systemic bone loss leading to greater fracture risk at all skeletal sites. In this study we investigated systemic bone loss and recovery following femoral fracture in young (3 month old) and middle-aged (12 month old) mice. Transverse femur fractures were created using a controlled impact, and whole-body bone mineral density (BMD), trabecular and cortical microstructure, bone mechanical properties, bone formation and resorption rates, mouse voluntary movement, and systemic inflammation were quantified at multiple time points post-fracture. We found that fracture led to decreased whole-body BMD in both young and middle-aged mice 2 weeks post-fracture; this bone loss was recovered by 6 weeks in young, but not middle-aged mice. Similarly, trabecular bone volume fraction (BV/TV) of the L5 vertebral body was significantly reduced in fractured mice relative to control mice 2 weeks post-fracture (−11% for young mice, −18% for middle-aged mice); this bone loss was fully recovered by 6 weeks post-fracture in young mice. At 3 days post-fracture we observed significant increases in serum levels of interleukin-6 and significant decreases in voluntary movement in fractured mice compared to control mice, with considerably greater changes in middle-aged mice than in young mice. At this time point we also observed increased osteoclast number on L5 vertebral body trabecular bone of fractured mice compared to control mice. These data show that systemic bone loss occurs after fracture in both young and middle-aged mice, and recovery from this bone loss may vary with age. This systemic response could contribute to increased future fracture risk following fracture, and these data may inform clinical treatment of fractures with respect to improving long-term skeletal health.

scholarly journals Blackcurrant Supplementation Improves Trabecular Bone Mass in Young but Not Aged Mice

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1671 ◽  
Author(s):  
Junichi Sakaki ◽  
Melissa Melough ◽  
Sang Lee ◽  
Judy Kalinowski ◽  
Sung Koo ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Chow Diet ◽  
Type I ◽  
Aged Mice ◽  
Age Related ◽  
Standard Chow Diet ◽  
Young Mice

Due to deleterious side effects of currently available medications, the search for novel, safe, and effective preventive agents for improving bone health in aging continues and is urgently needed. This study aimed to determine whether dietary blackcurrants (BC), an anthocyanin-rich berry, can improve bone mass in a mouse model of age-related bone loss. Thirty-five female C57BL/6J mice, 3 months old (n = 20) and 18 months old (n = 15), were randomized to consume either a standard chow diet or a standard chow diet with 1% (w/w) BC for four months. Dual-energy X-ray absorptiometry, Micro computed tomography (µCT), and histomorphometric analyses were conducted to assess bone parameters on femurs. Biochemical assays were conducted to determine bone resorption, antioxidant activity, and inflammation in humerus homogenates. Trabecular bone volume (BV/TV) was significantly lower in aged mice compared to young mice (young control, 3.7 ± 0.4% vs aged control, 1.5 ± 0.5%, mean ± SEM (standard error of mean), p < 0.01; young BC, 5.3 ± 0.6% vs aged BC, 1.1 ± 0.3%, p < 0.001). µCT analysis revealed that BC supplementation increased trabecular BV/TV in young mice by 43.2% (p < 0.05) compared to controls. Histomorphometric analysis revealed a 50% increase, though this effect was not statistically significant (p = 0.07). The osteoblast surface increased by 82.5% in aged mice with BC compared to controls (p < 0.01). In humerus homogenates of young mice, BC consumption reduced C-telopeptide of type I collagen by 12.4% (p < 0.05) and increased glutathione peroxidase by 96.4% (p < 0.05). In humerus homogenates of aged mice, BC consumption increased catalase by 12% (p = 0.09). Aged mice had significantly elevated concentrations of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine contributing to bone resorption, which was reduced by 43.3% with BC consumption (p = 0.06). These results suggest that early consumption of BC may protect from aging-associated bone loss.

scholarly journals Age-related trabecular bone loss is associated with a decline in serum Galectin-1 level

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wenting Xu ◽  
Cheng Ni ◽  
Yuxuan Wang ◽  
Guoqing Zheng ◽  
Jinshan Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Protein Expression ◽  
Trabecular Bone ◽  
Hematopoietic Stem ◽  
Aged Mice ◽  
Age Related ◽  
Trabecular Bone Loss ◽  
The Relationship ◽  
Young Mice

Abstract Background Senile osteoporosis with age-related bone loss is diagnosed depending on radiographic changes of bone and bone mineral density (BMD) measurement. However, radiographic alterations are usually signs of medium-late stage osteoporosis. Therefore, biomarkers have been proposed as indicators of bone loss. In the current study, Galectin-1 (Gal-1) showed age-related decline in mice serum. The role of Gal-1 in osteoporosis has not been investigated so far. Hence, the current study illustrated the relationship of serum Gal-1 level with bone loss. Methods We employed 6- and 18-month-old mice to establish an animal model of age-related trabecular bone loss, whose bone density and microstructure were investigated by micro-CT. ELISA was used to measure the levels of Gal-1 in serum. The correlation analysis was performed to illustrate the relationship between serum Gal-1 levels and trabecular bone loss. In addition, immunohistochemistry was used to investigate the abundance of Gal-1 in bone marrow of mice. ELISA and western blot were performed to measure the secretion ability and protein expression of Gal-1 in bone marrow stromal cells (BMSC), hematopoietic stem cells (HSC) and myeloid progenitor (MP) respectively. Flow cytometry was used to measure BMSC number in bone marrow. Finally, male volunteers with age-related BMD decrease were recruited and the relationship between serum Gal-1 and BMD was analyzed. Results Gal-1 showed age-related decline in mice serum. Serum Gal-1 was positively associated with BV/TV of femur, tibia and L1 vertebrae in mice. BMSC secreted more Gal-1 compared with HSC and MP. BMSC number in bone marrow was significantly lower in aged mice compared with young mice. Significant attenuation of Gal-1 protein expression was observed in BMSC and HSC from aged mice compared with young mice. Further, we found a decline in serum Gal-1 levels in men with age-related BMD decrease. There was positive correlation between BMD and serum Gal-1 levels in these men. Conclusions Age-related trabecular bone loss is associated with a decline in serum Gal-1 level in mice and men. Our study suggested Gal-1 had great potential to be a biomarker for discovering BMSC senescence, diagnosing early osteoporosis and monitoring trabecular bone loss.

scholarly journals Liver cytokine production and ICAM-1 expression following bone fracture, tissue trauma, and hemorrhage in middle-aged mice

2007 ◽  
Vol 292 (1) ◽  
pp. G268-G274 ◽  
Author(s):  
Takeshi Matsutani ◽  
Shih-Ching Kang ◽  
Masao Miyashita ◽  
Koji Sasajima ◽  
Mashkoor A. Choudhry ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Bone Fracture ◽  
Hepatic Damage ◽  
Middle Aged ◽  
Soft Tissue Trauma ◽  
Midline Laparotomy ◽  
Aged Mice ◽  
Lower Leg Fracture ◽  
Tissue Trauma ◽  
Young Mice

Although studies have indicated that hemorrhagic shock and resuscitation produces hepatic damage by mechanisms involving adhesion molecules in endothelial cells and hepatocytes, it is not known if there is any difference in the extent of hepatic damage following bone fracture, soft tissue trauma, and hemorrhage (Fx-TH) between young and middle-aged animals. To study this, young (6–8 wk) and middle-aged (∼12 mo) C3H/HeN male mice were subjected to a right lower leg fracture, soft tissue trauma, (i.e., midline laparotomy), and hemorrhage (blood withdrawal to decrease the blood pressure to 35 ± 5 mmHg for 90 min) followed by resuscitation with four times the shed blood volume in the form of lactated Ringer solution. Mice were euthanized 24 h later, and liver tissues were harvested. Total bilirubin levels in the hepatocyte extract increased markedly following Fx-TH in both groups of mice; however, the increase in middle-aged mice was significantly higher compared with young mice. TNF-α and IL-6 levels in the hepatocyte extract following Fx-TH increased significantly in middle-aged mice but remained unchanged in young mice. IL-10 levels significantly decreased in middle-aged mice following Fx-TH but remained unchanged in young mice. Kupffer cells from middle-aged mice produced significantly higher IL-6 and IL-10 levels compared with young mice. Protein levels and mRNA expression of ICAM-1 in hepatocytes were also significantly higher in middle-aged mice compared with young mice following Fx-TH. These results collectively suggest that the extent of hepatic damage following Fx-TH is dependent on the age of the subject.

scholarly journals Protective Effects of Curcumin and Broccoli Seed Extract Against Age-Related Bone Loss in Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 46-46
Author(s):  
Jing Li ◽  
Dong Zhang ◽  
Yiping Ren ◽  
Zhongdong Qiao ◽  
Doug Stevenson ◽  
...  
Keyword(s):  
Bone Loss ◽  
Seed Extract ◽  
Control Group ◽  
Protective Effects ◽  
Trabecular Thickness ◽  
Time Points ◽  
Aged Mice ◽  
Funding Sources ◽  
Age Related ◽  
Young Mice

Abstract Objectives Age-related bone loss occurs in both men and women, and is the leading cause of elderly disability. An age-related bone loss model was established in mice to investigate the protective effects of curcumin and broccoli seed extract. Methods 20 young (6-month-old) male C57BL/6 J mice after administration with vehicle once daily were sacrificed at four time points: day 0, 30, 60 and 90. 8 out of the 109 aged (18-month-old) male C57BL/6 J mice were sacrificed at the beginning and used as control. The rest of these aged mice were then randomly divided into four groups: one group served as control (vehicle), the other three groups were administrated with curcumin (CMN) and/or broccoli seed extract (BSE) by oral gavage. Mice in each group were sacrificed at four time points: day 0, 30, 60 and 90. L2 vertebrae of mice were fixed with paraformaldehyde and scanned with a Scanco Medical μCT40 scanner. Quantitative analyses of bone volume (BV), tissue volume (TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular spacing (Tb.Sp) were performed with the Scanco Medical's software. Results BV/TV of the young mice group were significantly higher compared to the aged mice group at all four time points. Similarly, Tb.N and Tb.Th were also higher in the young mice group compared to the aged mice group. In contrast, Tb.Sp was lower in the young mice group. When comparing different groups in the aged mice, we found that mice administered with CMN had a higher BV/TV value compared to the mice in the control group at all three time points. Such a difference is significant by day 30. The mice administered with combined CMN and BSE also showed significant increase in BV/TV on day 30. For Tb.N, both mice administered with either CMN or BSE had higher values at all three time points. But no obvious difference in Tb.N was found for mice administered with combined CMN and BSE. For Tb.Th, both mice administered with CMN and with combined CMN and BSE had higher values compared to the control. For Tb.Sp, both mice administered with either CMN or BSE had lower values compared to the control. Conclusions This study showed that curcumin could slow down bone loss in the mouse model. There is no obvious positive effect with broccoli seed extract or with curcumin and broccoli seed extract combined. The curcumin used in this study may shed light on the alleviation of bone loss in humans. Funding Sources Nu Skin Enterprises.

High-resolution peripheral quantitative computed tomography (HR-pQCT) to detect compartmental bone loss on androgen deprivation therapy (ADT): A feasibility study.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 209-209
Author(s):  
Rahul Raj Aggarwal ◽  
Tammy J. Rodvelt ◽  
Dora Tao ◽  
Jeffrey Hough ◽  
Miles Thomas ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Density ◽  
Bone Loss ◽  
Fracture Risk ◽  
Bone Metastases ◽  
Trabecular Bone ◽  
Quantitative Computed Tomography ◽  
Cross Sectional ◽  
Clinical Variables ◽  
Rank Correlation Method

209 Background: ADT causes bone loss, yet standard bone density (DXA) measurements do not distinguish cortical vs. trabecular bone loss and are falsely elevated in patients (pts) with sclerotic metastases, potentially underestimating fracture risk. HR-pQCT of the tibia and radius is a validated method to assess compartmental bone density and architecture that may overcome these limitations. Methods: Cross-sectional study of prostate cancer pts who underwent HR-pQCT (Scanco XtremeCT) of the radius and tibia and DXA scans within 6 months of initiating ADT. The relationship between HR-pQCT and relevant clinical variables was assessed using Spearman’s rank correlation method. Results: 22 pts were enrolled. Median baseline characteristics included: age = 64.5 (range 53-90), serum testosterone (T) level = 17 ng/dL (6-978), and interval between ADT start and HR-pQCT = 1.6 months (0-5.7). 5 pts (23%) were osteopenic as assessed by DXA. The correlation between HR-pQCT and clinical variables in shown in the Table. Of 12 pts with bone metastases, 7 (58%) had DXA L-spine and/or hip t-scores > 2 standard deviations above mean for 30 year-old male. In contrast, all 7 pts had HR-pQCT measurements within the expected range based on age, sex, and serum T. Conclusions: HR-pQCT to assess bone loss in prostate cancer pts on ADT is feasible. Radial trabecular bone volume and density are correlated with relevant clinical variables including ADT duration and serum T. In pts with bone metastases, HR-pQCT may provide more accurate means to estimate BMD and determine fracture risk. Longitudinal studies in pts on ADT with paired HR-pQCT scans are ongoing. Clinical trial information: NCT02168062. [Table: see text]

scholarly journals Susceptibility to chronic immobilization stress‐induced depressive-like behaviour in middle‐aged female mice and accompanying changes in dopamine D1 and GABAA receptors in related brain regions

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Guofen Cao ◽  
Gaili Meng ◽  
Li Zhu ◽  
Jie Zhu ◽  
Nan Dong ◽  
...  
Keyword(s):  
Immobilization Stress ◽  
Forced Swim Test ◽  
Preference Test ◽  
Brain Regions ◽  
Mrna Levels ◽  
Middle Aged ◽  
Aged Mice ◽  
Immobility Time ◽  
Chronic Immobilization Stress ◽  
Young Mice

Abstract Background Middle-aged females, especially perimenopausal females, are vulnerable to depression, but the potential mechanism remains unclear. Dopaminergic and GABAergic system dysfunction is involved in the pathophysiology of depression. In the current study, we used 2-month-old and 11-month-old C57BL/6 mice as young and middle-aged mice, respectively. Chronic immobilization stress (CIS) was used to induce depressive-like behaviour, and the sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were used to assess these behaviours. We then measured the mRNA levels of dopamine receptor D1 (DRD1) and the GABAA receptors GABRA1, GABRB2 and GABRG2 in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Results We found that immobility time in the FST was significantly increased in the middle-aged mice compared with the middle-aged control mice and the young mice. In addition, the preference for sucrose water was reduced in the middle-aged mice compared with the middle-aged control mice. However, CIS did not induce obvious changes in the performance of the young mice in our behavioural tests. Moreover, the middle-aged mice exhibited equal immobility times as the young mice in the absence of stress. Decreases in the mRNA levels of DRD1, GABRA1, and GABRB2 but not GABRG2 were found in the NAc and PFC in the middle-aged mice in the absence of stress. Further decreases in the mRNA levels of DRD1 in the NAc and GABRG2 in the NAc and PFC were found in the middle-aged mice subjected to CIS. Conclusions Our results suggested that ageing could not directly induce depression in the absence of stress. However, ageing could induce susceptibility to depression in middle-aged mice in the presence of stress. CIS-induced decreases in DRD1 and GABRG2 levels might be involved in the increase in susceptibility to depression in this context.

scholarly journals Unraveling Heterogeneity of Aged Hematopoietic Stem Cells By Single-Cell RNA Sequence Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4299-4299
Author(s):  
Shuhei Koide ◽  
Motohiko Oshima ◽  
Akira Nishiyama ◽  
Koichi Murakami ◽  
Yuta Yamada ◽  
...  
Keyword(s):  
Stem Cells ◽  
Sequence Analysis ◽  
Hematopoietic Stem Cells ◽  
Single Cell ◽  
Gene Signature ◽  
Middle Aged ◽  
Hematopoietic Stem ◽  
Rna Sequence ◽  
Aged Mice ◽  
Young Mice

Abstract During aging, hematopoietic stem cells (HSCs) alter quantitatively as well as qualitatively due to accumulating damages induced by intrinsic and extrinsic stresses. Functional decline of HSCs causes deregulated hematopoiesis resulting in anemia, immune dysfunction, and increased risk of hematologic malignancies. The absolute number of HSCs in aged mice evidently increases compared to young mice. In addition, aged HSCs show abnormal hematopoiesis such as myeloid-biased differentiation accompanied by low production of lymphocytes. However, the molecular mechanisms underlying age-associated changes in hematopoiesis remain largely unknown. In this study, we performed single-cell RNA sequence analysis (scRNA-seq) of HSCs from young (10-week-old), middle-aged (12-month-old) and aged (20-month-old) mice to gain insight into the dynamics of HSC aging. scRNA-seq analysis revealed three major clusters (A, B, C) and three minor clusters (D, E, F) in young HSCs. Of interest, aged HSCs also showed similar cluster formation. One of the minor clusters was characterized by gene signature associated with inflammatory response and significantly increased with age, while the remaining two minor clusters, which showed cell cycle gene signature, did not change in proportion. One of the major clusters, Cluster C, which showed the strongest expression of HSC-specific gene sets compared with other clusters, moderately increased with age. Our scRNA-seq analysis confirmed upregulation of age-related genes previously reported, such as Selp, Mt1, and Vwf, in a considerable portion of aged HSCs. von Willebrand factor (Vwf) encodes a blood glycoprotein produced by megakaryocytes and endothelial cells. Several groups have reported that Vwf-expressing HSCs show myeloid/platelet-biased differentiation (Joana C et al., Nature 2013; Sandra P et al., Developmental Cell 2018). Importantly, our scRNA-seq data identified that Clusterin (Clu) is rarely expressed in young HSCs and is dramatically upregulated in aged HSCs. Clu expression was predominantly increased in one of the major clusters, Cluster C. Clusterin encodes a secreted chaperone involved in clearance of cellular debris and regulation of apoptosis. We hypothesized that Clu would be useful as a marker of a unique subpopulation of aged HSCs, and thus conducted further analysis by using Clu reporter mice with Clu BAC clone, in which an EGFP reporter gene was inserted at the initiating ATG codon of the Clu gene so that EGFP expression is driven by the regulatory sequences of the BAC gene. Clu/GFP was preferentially expressed in HSCs and at lower frequencies in MPP1 than HSCs in Lineage -Sca-1 +c-Kit + (LSK) cell fraction. Clu-positive HSCs expressed high levels of CD150 and were detected in 10% and 60% of HSCs in 10-week-old young mice and 8-month-old middle-aged mice, respectively, indicating that Clu-positive HSCs increase with aging. We next assessed the function of Clu-positive HSCs in young mice. Clu-positive young HSCs established significantly lower chimerism than Clu-negative young HSCs and preferentially differentiated into myeloid cells in competitive transplantation assays. RNA-seq analysis of Clu-positive and Clu-negative HSCs from young mice confirmed that Clu-positive HSCs show the gene signature of myeloid-biased HSCs. Characterization of Clu-positive and negative subpopulations in aged HSCs is currently underway. These results suggest that Clu-positive HSCs represent myeloid-biased HSCs which expand with aging, thus Clu expression serves as a novel marker to monitor the alterations in HSC heterogeneity with aging. Disclosures Iwama: Nissan Chemical Corporation: Research Funding.

Age-dependent hypothalamic expression of neuropeptides in wild-type and melanocortin-4 receptor-deficient mice

2003 ◽  
Vol 16 (1) ◽  
pp. 38-46 ◽  
Author(s):  
Janine Arens ◽  
Kim M. Moar ◽  
Sandra Eiden ◽  
Karin Weide ◽  
Ingrid Schmidt ◽  
...  
Keyword(s):  
Body Fat ◽  
Fat Content ◽  
Wild Type ◽  
Middle Aged ◽  
Aged Mice ◽  
Melanocortin 4 Receptor ◽  
Body Fat Content ◽  
Age Dependent ◽  
Deficient Mice ◽  
Young Mice

In young (35- to 56-day-old) and middle-aged (9-mo-old) wild-type (+/+) and melanocortin-4 receptor (MC4R)-deficient (+/−, −/−) mice, expressions of neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin (POMC), and cocaine-and-amphetamine-regulated transcript (CART) were analyzed in the arcuate nucleus (ARC) and adjacent regions comprising the dorsomedial (DMN) and ventromedial (VMN) nucleus. In the ARC of young mice, NPY and AGRP expression increased and POMC and CART expression decreased with body fat content. Adjusting for the influence of body fat content by ANCOVA showed that the levels of NPY, POMC, and CART were highest and of AGRP lowest in young −/− mice. In the middle-aged mice, feedback from body fat content was weakened. For −/− mice ANCOVA revealed higher NPY and AGRP, lower POMC, and unchanged CART expression levels relative to young −/− mice. In the DMN and VMN, POMC and AGRP signals were absent at each age. CART was expressed in the DMN independent of age, fat content, and genotype. For NPY expression, an age-dependent induction was found in the DMN and VMN; it was absent in the young but present in the middle-aged mice, showing close positive correlations between body fat content and the numbers of NPY-labeled cells which were further enhanced in −/− mice. Thus MC4R deficiency augments age-induced NPY expression in the DMN and VMN with no feedback from body fat content. Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency.

scholarly journals The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice

2020 ◽  
Vol 8 ◽  
Author(s):  
Anuj K. Sharma ◽  
Rachel L. Roberts ◽  
Reginald D. Benson ◽  
Jessica L. Pierce ◽  
Kanglun Yu ◽  
...  
Keyword(s):  
Bone Loss ◽  
Trabecular Bone ◽  
Aged Mice ◽  
Trabecular Bone Loss
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