Effects of Long-Term Sclerostin Deficiency on Trabecular Bone Mass and Adaption to Limb Loading Differ in Male and Female Mice

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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Osteoblast-Specific Overexpression of Human WNT16 Increases Both Cortical and Trabecular Bone Mass and Structure in Mice

Endocrinology ◽

10.1210/en.2015-1281 ◽

2015 ◽

Vol 157 (2) ◽

pp. 722-736 ◽

Cited By ~ 22

Author(s):

Imranul Alam ◽

Mohammed Alkhouli ◽

Rita L. Gerard-O'Riley ◽

Weston B. Wright ◽

Dena Acton ◽

...

Keyword(s):

Gene Expression ◽

Bone Mass ◽

Trabecular Bone ◽

Bone Mineral ◽

Serum Biochemistry ◽

Whole Body ◽

Genome Wide Association Studies ◽

Bone Formation Rate ◽

Male And Female ◽

Trabecular Bone Mass

Abstract Previous genome-wide association studies have identified common variants in genes associated with bone mineral density (BMD) and risk of fracture. Recently, we identified single nucleotide polymorphisms (SNPs) in Wingless-type mouse mammary tumor virus integration site (WNT)16 that were associated with peak BMD in premenopausal women. To further identify the role of Wnt16 in bone mass regulation, we created transgenic (TG) mice overexpressing human WNT16 in osteoblasts. We compared bone phenotypes, serum biochemistry, gene expression, and dynamic bone histomorphometry between TG and wild-type (WT) mice. Compared with WT mice, WNT16-TG mice exhibited significantly higher whole-body areal BMD and bone mineral content (BMC) at 6 and 12 weeks of age in both male and female. Microcomputer tomography analysis of trabecular bone at distal femur revealed 3-fold (male) and 14-fold (female) higher bone volume/tissue volume (BV/TV), and significantly higher trabecular number and trabecular thickness but lower trabecular separation in TG mice compared with WT littermates in both sexes. The cortical bone at femur midshaft also displayed significantly greater bone area/total area and cortical thickness in the TG mice in both sexes. Serum biochemistry analysis showed that male TG mice had higher serum alkaline phosphatase, osteocalcin, osteoprotegerin (OPG), OPG to receptor activator of NF-kB ligand (tumor necrosis family ligand superfamily, number 11; RANKL) ratio as compared with WT mice. Also, lower carboxy-terminal collagen cross-link (CTX) to tartrate-resistant acid phosphatase 5, isoform b (TRAPc5b) ratio was observed in TG mice compared with WT littermates in both male and female. Histomorphometry data demonstrated that both male and female TG mice had significantly higher cortical and trabecular mineralizing surface/bone surface and bone formation rate compared with sex-matched WT mice. Gene expression analysis demonstrated higher expression of Alp, OC, Opg, and Opg to Rankl ratio in bone tissue in the TG mice compared with WT littermates. Our data indicate that WNT16 is critical for positive regulation of both cortical and trabecular bone mass and structure and that this molecule might be targeted for therapeutic interventions to treat osteoporosis.

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Chemokine receptor 3 is a negative regulator of trabecular bone mass in female mice

Journal of Cellular Biochemistry ◽

10.1002/jcb.28672 ◽

2019 ◽

Vol 120 (8) ◽

pp. 13974-13984 ◽

Cited By ~ 2

Author(s):

Subburaman Mohan ◽

Yan Hu ◽

Bouchra Edderkaoui

Keyword(s):

Bone Mass ◽

Trabecular Bone ◽

Chemokine Receptor ◽

Negative Regulator ◽

Female Mice ◽

Trabecular Bone Mass

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SERMs have substance-specific effects on bone, and these effects are mediated via ERαAF-1 in female mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00488.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. E912-E918 ◽

Cited By ~ 16

Author(s):

Anna E. Börjesson ◽

Helen H. Farman ◽

Sofia Movérare-Skrtic ◽

Cecilia Engdahl ◽

Maria Cristina Antal ◽

...

Keyword(s):

Bone Mass ◽

Trabecular Bone ◽

Axial Skeleton ◽

Activation Function ◽

Appendicular Skeleton ◽

Minor Effect ◽

Cortical Porosity ◽

Female Mice ◽

Trabecular Bone Mass

The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)α, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ERαAF-1 for the estradiol (E2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ERαAF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ERαAF-1 (ERαAF-10) with E2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ERαAF-10 mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ERαAF-1 in female mice. These results could lead to development of more specific treatments for osteoporosis.

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Quantitative computed tomography in measurement of vertebral trabecular bone mass

Acta Radiologica ◽

10.3109/02841858809171972 ◽

1988 ◽

Vol 29 (6) ◽

pp. 719-725 ◽

Cited By ~ 1

Author(s):

M. Nilsson ◽

O. Johnell ◽

K. Jonsson ◽

I. Redlund-Johnell

Keyword(s):

Computed Tomography ◽

Bone Mass ◽

Trabecular Bone ◽

Quantitative Computed Tomography ◽

Vertebral Trabecular Bone ◽

Trabecular Bone Mass

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Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Bone ◽

10.1016/j.bone.2015.08.006 ◽

2015 ◽

Vol 81 ◽

pp. 459-467 ◽

Cited By ~ 52

Author(s):

M. Pereira ◽

J. Jeyabalan ◽

C.S. Jørgensen ◽

M. Hopkinson ◽

A. Al-Jazzar ◽

...

Keyword(s):

Bone Mass ◽

Trabecular Bone ◽

Chronic Administration ◽

Receptor Agonists ◽

Trabecular Bone Mass ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Disruption of the p53 Gene Results in Preserved Trabecular Bone Mass and Bone Formation After Mechanical Unloading

Journal of Bone and Mineral Research ◽

10.1359/jbmr.2002.17.1.119 ◽

2002 ◽

Vol 17 (1) ◽

pp. 119-127 ◽

Cited By ~ 38

Author(s):

Akinori Sakai ◽

Takeshi Sakata ◽

Shinya Tanaka ◽

Ryuji Okazaki ◽

Naoki Kunugita ◽

...

Keyword(s):

Bone Formation ◽

Bone Mass ◽

Trabecular Bone ◽

P53 Gene ◽

Mechanical Unloading ◽

Trabecular Bone Mass

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Developmental exposure to silver nanoparticles leads to long term gut dysbiosis and neurobehavioral alterations

Scientific Reports ◽

10.1038/s41598-021-85919-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zhen Lyu ◽

Shreya Ghoshdastidar ◽

Karamkolly R. Rekha ◽

Dhananjay Suresh ◽

Jiude Mao ◽

...

Keyword(s):

Silver Nanoparticles ◽

Body Fat ◽

Repetitive Behaviors ◽

Developmental Exposure ◽

Male And Female ◽

Female Mice ◽

Gut Dysbiosis ◽

Study Results ◽

Wide Range

AbstractDue to their antimicrobial properties, silver nanoparticles (AgNPs) are used in a wide range of consumer products that includes topical wound dressings, coatings for biomedical devices, and food-packaging to extend the shelf-life. Despite their beneficial antimicrobial effects, developmental exposure to such AgNPs may lead to gut dysbiosis and long-term health consequences in exposed offspring. AgNPs can cross the placenta and blood–brain-barrier to translocate in the brain of offspring. The underlying hypothesis tested in the current study was that developmental exposure of male and female mice to AgNPs disrupts the microbiome–gut–brain axis. To examine for such effects, C57BL6 female mice were exposed orally to AgNPs at a dose of 3 mg/kg BW or vehicle control 2 weeks prior to breeding and throughout gestation. Male and female offspring were tested in various mazes that measure different behavioral domains, and the gut microbial profiles were surveyed from 30 through 120 days of age. Our study results suggest that developmental exposure results in increased likelihood of engaging in repetitive behaviors and reductions in resident microglial cells. Echo-MRI results indicate increased body fat in offspring exposed to AgNPs exhibit. Coprobacillus spp., Mucispirillum spp., and Bifidobacterium spp. were reduced, while Prevotella spp., Bacillus spp., Planococcaceae, Staphylococcus spp., Enterococcus spp., and Ruminococcus spp. were increased in those developmentally exposed to NPs. These bacterial changes were linked to behavioral and metabolic alterations. In conclusion, developmental exposure of AgNPs results in long term gut dysbiosis, body fat increase and neurobehavioral alterations in offspring.

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Prolyl Hydroxylase Domain-Containing Protein 3 Gene Expression in Chondrocytes Is Not Essential for Bone Development in Mice

Cells ◽

10.3390/cells10092200 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2200

Author(s):

Weirong Xing ◽

Sheila Pourteymoor ◽

Gustavo A. Gomez ◽

Yian Chen ◽

Subburaman Mohan

Keyword(s):

Gene Expression ◽

Bone Formation ◽

Bone Mass ◽

Trabecular Bone ◽

Bone Volume ◽

Endochondral Bone Formation ◽

Chondrocyte Differentiation ◽

Trabecular Bone Volume ◽

Endochondral Bone ◽

Trabecular Bone Mass

We previously showed that conditional disruption of the Phd2 gene in chondrocytes led to a massive increase in long bone trabecular bone mass. Loss of Phd2 gene expression or inhibition of PHD2 activity by a specific inhibitor resulted in a several-fold compensatory increase in Phd3 expression in chondrocytes. To determine if expression of PHD3 plays a role in endochondral bone formation, we conditionally disrupted the Phd3 gene in chondrocytes by crossing Phd3 floxed (Phd3flox/flox) mice with Col2α1-Cre mice. Loss of Phd3 expression in the chondrocytes of Cre+; Phd3flox/flox conditional knockout (cKO) mice was confirmed by real time PCR. At 16 weeks of age, neither body weight nor body length was significantly different in the Phd3 cKO mice compared to Cre−; Phd3flox/flox wild-type (WT) mice. Areal BMD measurements of total body as well as femur, tibia, and lumbar skeletal sites were not significantly different between the cKO and WT mice at 16 weeks of age. Micro-CT measurements revealed significant gender differences in the trabecular bone volume adjusted for tissue volume at the secondary spongiosa of the femur and the tibia for both genotypes, but no genotype difference was found for any of the trabecular bone measurements of either the femur or the tibia. Trabecular bone volume of distal femur epiphysis was not different between cKO and WT mice. Histology analyses revealed Phd3 cKO mice exhibited a comparable chondrocyte differentiation and proliferation, as evidenced by no changes in cartilage thickness and area in the cKO mice as compared to WT littermates. Consistent with the in vivo data, lentiviral shRNA-mediated knockdown of Phd3 expression in chondrocytes did not affect the expression of markers of chondrocyte differentiation (Col2, Col10, Acan, Sox9). Our study found that Phd2 but not Phd3 expressed in chondrocytes regulates endochondral bone formation, and the compensatory increase in Phd3 expression in the chondrocytes of Phd2 cKO mice is not the cause for increased trabecular bone mass in Phd2 cKO mice.

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Adolescent intermittent ethanol exposure induces sex-dependent divergent changes in ethanol drinking and motor activity in adulthood in C57BL/6J mice

10.1101/2020.04.28.066472 ◽

2020 ◽

Cited By ~ 1

Author(s):

Antoniette M. Maldonado-Devincci ◽

Joseph G. Makdisi ◽

Andrea M. Hill ◽

Renee C. Waters ◽

Nzia I. Hall ◽

...

Keyword(s):

Open Field ◽

Ethanol Consumption ◽

Ethanol Exposure ◽

Male Mice ◽

Open Field Behavior ◽

Male And Female ◽

Female Mice ◽

Binge Ethanol Exposure ◽

Binge Ethanol

AbstractWith alcohol readily accessible to adolescents, its consumption leads to many adverse effects, including impaired learning, attention, and behavior. Adolescents report higher rates of binge drinking compared to adults. Adolescents are also more prone to substance use disorder during adulthood due to physiological changes during the adolescent developmental period. We used C57BL/6J male and female mice to investigate the long-lasting impact of binge ethanol exposure during adolescence on voluntary ethanol intake and open field behavior during later adolescence and in young adulthood. The present set of experiments were divided into four stages: (1) chronic intermittent vapor inhalation exposure, (2) abstinence, (3) voluntary ethanol intake, and (4) open field behavioral testing. During adolescence, male and female mice were exposed to air or ethanol using an intermittent vapor inhalation with repeated binge pattern ethanol exposure from postnatal day (PND) 28–42. Following this, mice underwent abstinence during late adolescence from PND 43–49 (Experiment 1) or PND 43–69 (Experiment 2). Beginning on PND 49–76 (Experiment 1) or PND 70–97 (Experiment 2), mice were assessed for intermittent voluntary ethanol consumption using a two-bottle drinking procedure over 28 days. Male mice that were exposed to ethanol during adolescence showed increased ethanol consumption during later adolescence (Experiment 1) and in emerging adulthood (Experiment 2), while the female mice showed decreased ethanol consumption. These data demonstrate a sexually divergent shift in ethanol consumption following binge ethanol exposure during adolescence and differences in open field behavior. These data highlight sex-dependent vulnerability to developing substance use disorders in adulthood.Significance StatementCurrently, it is vital to determine the sex-dependent impact of binge alcohol exposure during adolescence, given that until recently females have largely been ignored. Here we show that adolescent male mice that are exposed to binge ethanol during adolescence show long-term changes in behavior in adulthood. In contrast, female mice show a transient decrease in ethanol consumption in adulthood and decreased motor activity spent in the center zone of the open field test. Male mice appear to be more susceptible to the long-term changes in ethanol consumption following binge ethanol exposure during adolescence.

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