Glucocorticoid-induced loss of cortical bone is exacerbated during cold-exposure in male mice

Parathyroid hormone (PTH) exerts both catabolic and anabolic actions on bone. Studies on the skeletal effects of PTH have seldom considered the effects of gender. Our study was designed to determine whether the response of mouse bone to PTH differed according to sex. As a first step, we analyzed gender differences with respect to bone mass and structural properties of 4 month old PTH treated (80 μg/kg per day for 2 weeks) male and female CD-1 mice. PTH significantly increased fat free weight/body weight, periosteal bone formation rate, mineral apposition rate, and endosteal single labeling surface, while significantly decreasing medullary area in male mice compared with vehicle treated controls, but induced no significant changes in female mice. We then analyzed the gender differences in bone marrow stromal cells (BMSC) isolated from 4 month old male and female CD-1 mice following treatment with PTH (80 μg/kg per day for 2 weeks). PTH significantly increased the osteogenic colony number and the alkaline phosphatase (ALP) activity (ALP/cell) by day 14 in cultures of BMSCs from male and female mice. PTH also increased the mRNA level of receptor activator of nuclear factor κB ligand in the bone tissue (marrow removed) of both females and males. However, PTH increased the mRNA levels of IGF-I and IGF-IR only in the bones of male mice. Our results indicate that on balance a 2-weeks course of PTH is anabolic on cortical bone in this mouse strain. These effects are more evident in the male mouse. These differences between male and female mice may reflect the greater response to PTH of IGF-I and IGF-IR gene expression in males enhancing the anabolic effect on cortical bone.

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Cortical bone adaptation to a moderate level of mechanical loading in male Sost deficient mice

Scientific Reports ◽

10.1038/s41598-020-79098-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Haisheng Yang ◽

Alexander Büttner ◽

Laia Albiol ◽

Catherine Julien ◽

Tobias Thiele ◽

...

Keyword(s):

Physical Activity ◽

Bone Formation ◽

Bone Mass ◽

Cortical Bone ◽

Bone Adaptation ◽

Moderate Level ◽

Skeletal Maturation ◽

Male Mice ◽

Males And Females

AbstractLoss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 με at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 με at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

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CCR3 deficiency is associated with increased osteoclast activity and reduced cortical bone volume in adult male mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015571 ◽

2020 ◽

pp. jbc.RA120.015571

Author(s):

Sara Rosendahl ◽

Rima Sulniute ◽

Michaela Eklund ◽

Cecilia Koskinen Holm ◽

Marcus J. O. Johansson ◽

...

Keyword(s):

Mrna Expression ◽

Cortical Bone ◽

Bone Remodeling ◽

Adult Male ◽

Chemokine Receptors ◽

Osteoclast Formation ◽

Male Mice ◽

Primary Mouse ◽

Deficient Mice

Increasing evidence emphasizes the importance of chemokines and chemokine receptors as regulators of bone remodeling. The C-C chemokine receptor 3 (CCR3) is dramatically up-regulated during osteoclastogenesis but the role of CCR3 in osteoclast formation and bone remodeling in adult mice is unknown. Herein, we used bone marrow macrophages (BMM) derived from adult male CCR3-proficient and -deficient mice to study the role of CCR3 in osteoclast formation and activity. CCR3 deficiency was associated with formation of giant hypernucleated osteoclasts, enhanced bone resorption when cultured on bone slices and altered mRNA expression of related chemokine receptors and ligands. Additionally, primary mouse calvarial osteoblasts isolated from CCR3-deficient mice showed increased mRNA expression of the osteoclast activator related gene, receptor activator of nuclear factor kappa-B ligand (Rankl), and osteoblast differentiation associated genes. Micro-computed tomography analyses of femurs from CCR3-deficient mice revealed a bone phenotype that entailed less cortical thickness and volume. Consistent with our in vitro studies, the number of osteoclasts did not differ between the genotypes in vivo. Moreover, an increased endo-cortical osteoid mineralization rate and higher trabecular and cortical bone formation rate was displayed in CCR3-deficient mice. Collectively, our data show that CCR3 deficiency influences osteoblast and osteoclast differentiation and that it is associated with thinner cortical bone in adult male mice.

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Cortical bone gain following loading is site-specifically enhanced by prior and concurrent disuse in aged male mice

10.1101/705640 ◽

2019 ◽

Author(s):

Gabriel Galea ◽

Peter J Delisser ◽

Lee Meakin ◽

Lance E Lanyon ◽

Joanna S Price ◽

...

Keyword(s):

Bone Mass ◽

Cortical Bone ◽

List Type ◽

Male Mice ◽

Site Specific ◽

Female Mice ◽

Age Related ◽

Sciatic Neurectomy ◽

Bone Gain ◽

Old Mice

AbstractThe primary aim of bone anabolic therapies is to strategically increase bone mass in skeletal regions likely to experience high strains. This is naturally achieved by mechanical loading of the young healthy skeleton. However, these bone anabolic responses fail with age. Here, we applied site specificity analysis to map regional differences in bone anabolic responses to axial loading of the tibia (tri-weekly, for two weeks) between young (19-week-old) and aged (19-month-old), male and female mice. Loading increased bone mass specifically in the proximal tibia in both sexes and ages. Young female mice gained more cortical bone than young males in specific regions of the tibia. However, these site-specific sex difference were lost with age such that bone gain following loading was not significantly different between old males and females. Having previously demonstrated that prior and concurrent disuse enhances bone gain following loading in old females, we established whether this “rescue” is sex-specific. Old male mice were subjected to sciatic neurectomy or sham surgery, and tri-weekly loading was initiated four days after surgery. Disuse augmented cortical bone gain in response to loading in old male mice, but only in the regions of the tibia which were load-responsive in the young. Increased understanding of how locally-activated load-responsive processes lead to site-specific bone formation, and how the age-related diminution of these processes can be site-specifically enhanced by disuse, may lead to the next generation of strategic bone anabolic therapies.HighlightsSex differences in cortical tissue area of young and old mice are not site-specificThe loading response in young, but not old, mice is sex- and site-specificThe cortical loading response is site-specifically enhanced by disuse in old mice of both sexesThe trabecular loading response can be rescued by disuse in old male, but not female, mice

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Adenine-induced chronic kidney disease induces a similar skeletal phenotype in male and female C57BL/6 mice with more severe deficits in cortical bone properties of male mice

PLoS ONE ◽

10.1371/journal.pone.0250438 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0250438

Author(s):

Corinne E. Metzger ◽

Elizabeth A. Swallow ◽

Alexander J. Stacy ◽

Matthew R. Allen

Keyword(s):

Mechanical Properties ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Bone Turnover ◽

Cortical Bone ◽

Male Mice ◽

Male And Female ◽

High Bone Turnover ◽

Female Mice ◽

High Bone

Chronic kidney disease (CKD) causes bone loss, particularly in cortical bone, through formation of cortical pores which lead to skeletal fragility. Animal models of CKD have shown variability in the skeletal response to CKD between males and females suggesting sex may play a role in this variation. Our aim was to compare the impact of adenine-induced CKD on cortical parameters in skeletally mature male and female C57Bl/6 mice. After 10-weeks of adenine-induced CKD, both male and female adenine mice had high serum parathyroid hormone (PTH), high bone turnover, and cortical porosity compared to non-CKD controls. Both sexes had lower cortical thickness, but only male mice had lower cortical bone area. CKD imparted greater deficits in mechanical properties of male mice compared to female mice. These data demonstrate that both male and female mice develop high PTH/high bone turnover in response to adenine-induced CKD and that cortical bone phenotypes are slightly more severe in males, particularly in mechanical properties deficits.

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Micro-architectural changes in cancellous bone differ in female and male C57BL/6 mice with high-fat diet-induced low bone mineral density

British Journal Of Nutrition ◽

10.1017/s0007114514000051 ◽

2014 ◽

Vol 111 (10) ◽

pp. 1811-1821 ◽

Cited By ~ 35

Author(s):

Jyoti Gautam ◽

Dharmendra Choudhary ◽

Vikram Khedgikar ◽

Priyanka Kushwaha ◽

Ravi Shankar Singh ◽

...

Keyword(s):

Bone Mass ◽

Cortical Bone ◽

Cancellous Bone ◽

High Fat Diet ◽

Female Rats ◽

Male Mice ◽

High Fat ◽

Mineral Density ◽

Collagen Crosslinks ◽

Males And Females

The relationship between fat and bone mass at distinct trabecular and cortical skeletal compartments in a high-fat diet (HFD) model was studied. For this, C57BL/6 mice were assigned to four groups of eight animals each. Two groups, each of males and females, received a standard chow diet while the remaining other two groups received the HFD for a period of 10 weeks. Male mice on the HFD were heavier and gained more weight (15·8 %; P< 0·05) v. those on the control diet or when compared with the female rats fed the HFD. We observed an increased lipid profile in both males and females, with significantly higher lipid levels (about 20–25 %; P< 0·01) in males. However, glucose intolerance was more pronounced in females than males on the HFD (about 30 %; P< 0·05). The micro-architectural assessment of bones showed that compared with female mice on the HFD, male mice on the HFD showed more deterioration at the trabecular region. This was corroborated by plasma osteocalcin and carboxy-terminal collagen crosslinks (CTx) levels confirming greater loss in males (about 20 %; P< 0·01). In both sexes cortical bone parameters and strength remained unchanged after 10 weeks of HFD treatment. The direct effect of the HFD on bone at the messenger RNA level in progenitor cells isolated from femoral bone marrow was a significantly increased expression of adipogenic marker genes v. osteogenic genes. Overall, the present data indicate that obesity induced by a HFD aggravates bone loss in the cancellous bone compartment, with a greater loss in males than females, although 10 weeks of HFD treatment did not alter cortical bone mass and strength in both males and females.

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Metformin Affects Cortical Bone Mass and Marrow Adiposity in Diet-Induced Obesity in Male Mice

Endocrinology ◽

10.1210/en.2017-00299 ◽

2017 ◽

Vol 158 (10) ◽

pp. 3369-3385 ◽

Cited By ~ 22

Author(s):

Sheila Bornstein ◽

Michele Moschetta ◽

Yawara Kawano ◽

Antonio Sacco ◽

Daisy Huynh ◽

...

Keyword(s):

Bone Mass ◽

Cortical Bone ◽

Male Mice ◽

Diet Induced Obesity ◽

Marrow Adiposity ◽

Cortical Bone Mass

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5-Thio-D-glucose: hypothermic responses in mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1980.239.3.r214 ◽

1980 ◽

Vol 239 (3) ◽

pp. R214-R218 ◽

Cited By ~ 2

Author(s):

R. Francesconi ◽

M. Mager

Keyword(s):

Food Deprivation ◽

Adult Male ◽

Rectal Temperature ◽

Cold Exposure ◽

Competitive Inhibition ◽

Male Mice ◽

Inhibition Of Glycolysis ◽

Environmental Temperatures ◽

Dose Dependent ◽

Circulating Levels

Adult male mice were administered several doses of 5-thio-D-glucose (5-TG) at two environmental temperatures, 4 and 22 degrees C. Both intracerebroventricular (icv) and intraperitoneal (ip) administration of 5-TG resulted in significant (P < 0.05 to P < 0.001) decrements in rectal temperature (Tre) that were dose dependent. After 30 min, the hypothermic effects were significantly (P < 0.001, icv, 100 microgram) exacerbated by cold exposure (4 vs. 22 degrees C) and were likewise intensified significantly (P < 0.005, 45 min, fed vs. 18 h fasted) by food deprivation. These reductions in Tre were accompanied by significant (P < 0.001) increases in circulating levels of glucose. The present results indicate that 5-TG may be eliciting both central and peripheral cellular glucopenia concomitant with circulatory hyperglycemia; thus, the resultant hypothermia may be arising from competitive inhibition of glycolysis by 5-TG intermediates as well as reduced availability of tissue glucose.

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