The cyclooxygenase-2 selective inhibitor NS-398 does not influence trabecular or cortical bone gain resulting from repeated mechanical loading in female mice

Accumulating evidence indicates that estrogen receptors (ERs) are involved in the mechano-adaptive mechanisms by which loading influences the mass and architecture of bones to establish and maintain their structural load-bearing competence. In the present study, we assessed the effects of the ER modulators tamoxifen and fulvestrant (ICI 182,780) on loading-related changes in the volume and structure of trabecular and cortical bone in the tibiae of female mice. Ten days after actual or sham ovariectomy, 17-wk-old female C57BL/6 mice were treated with vehicle (peanut oil), tamoxifen (0.02, 0.2, or 2 mg/kg · d), fulvestrant (4 mg/kg · d), or their combination and the right tibiae subjected to a short period of noninvasive axial loading (40 cycles/d) on 5 d during the subsequent 2 wk. In the left control tibiae, ovariectomy, tamoxifen, or fulvestrant did not have any significant effect on cortical bone volume, whereas trabecular bone volume was decreased by ovariectomy, increased by tamoxifen, and unaffected by fulvestrant. In the right tibiae, loading was associated with increases in both trabecular and cortical bone volume. Notably, the medium dose of tamoxifen synergistically enhanced loading-related gain in trabecular bone volume through an increase in trabecular thickness. Fulvestrant had no influence on the effects of loading but abrogated the enhancement of loading-related bone gain by tamoxifen. These data demonstrate that, at least in female mice, the adaptive response to mechanical loading of trabecular bone can be enhanced by ER modulators, in this case by tamoxifen.

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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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Faculty Opinions recommendation of Mechanical loading enhances the anabolic effects of intermittent parathyroid hormone (1-34) on trabecular and cortical bone in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1117765.573840 ◽

2008 ◽

Author(s):

Chantal Chenu

Keyword(s):

Parathyroid Hormone ◽

Cortical Bone ◽

Mechanical Loading

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Gender differences in the response of CD-1 mouse bone to parathyroid hormone: potential role of IGF-I

Journal of Endocrinology ◽

10.1677/joe.1.06351 ◽

2006 ◽

Vol 189 (2) ◽

pp. 279-287 ◽

Cited By ~ 20

Author(s):

Yongmei Wang ◽

Takeshi Sakata ◽

Hashem Z Elalieh ◽

Scott J Munson ◽

Andrew Burghardt ◽

...

Keyword(s):

Gender Differences ◽

Parathyroid Hormone ◽

Cortical Bone ◽

Mineral Apposition Rate ◽

Mrna Levels ◽

Male Mice ◽

Bone Formation Rate ◽

Male And Female ◽

Female Mice ◽

Igf I

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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MIDKINE DEFICIENCY INCREASES THE ANABOLIC RESPONSE OF CORTICAL BONE TO MECHANICAL LOADING

Journal of Biomechanics ◽

10.1016/s0021-9290(12)70092-1 ◽

2012 ◽

Vol 45 ◽

pp. S91

Author(s):

Astrid Liedert ◽

Laura Mattausch ◽

Daniel Vogele ◽

Marcus Pahl ◽

Ronny Bindl ◽

...

Keyword(s):

Cortical Bone ◽

Mechanical Loading ◽

Anabolic Response

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Mutation of the Galectin-3 Glycan Binding Domain (Lgals3-R200S) Enhances Cortical Bone Expansion in Male and Trabecular Bone Mass in Female Mice

10.1101/2020.01.09.900787 ◽

2020 ◽

Author(s):

Kevin A. Maupin ◽

Daniel Dick ◽

VARI Vivarium ◽

Transgenics Core ◽

Bart O. Williams

Keyword(s):

Bone Mass ◽

Trabecular Bone ◽

Cortical Bone ◽

Mutant Mice ◽

Slight Variation ◽

Female Mice ◽

Bone Phenotype ◽

Bone Expansion ◽

Galectin 3 ◽

Trabecular Bone Mass

AbstractThe study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.

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