8E-02 Influence of Mechanical Vibration on Bone Mass and Morphology of Female Mice with Different Age

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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Brain‐Derived Acetylcholine Maintains Peak Bone Mass in Adult Female Mice

Journal of Bone and Mineral Research ◽

10.1002/jbmr.4024 ◽

2020 ◽

Vol 35 (8) ◽

pp. 1562-1571

Author(s):

Yun Ma ◽

Florent Elefteriou

Keyword(s):

Bone Mass ◽

Adult Female ◽

Peak Bone Mass ◽

Female Mice

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The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+–NFATc1 axis

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.012023 ◽

2020 ◽

Vol 295 (19) ◽

pp. 6629-6640 ◽

Cited By ~ 2

Author(s):

Anna Ballard ◽

Rong Zeng ◽

Allahdad Zarei ◽

Christine Shao ◽

Linda Cox ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Bone Mass ◽

Intracellular Signaling ◽

Osteoclast Differentiation ◽

Calcium Entry ◽

Calcium Handling ◽

Mitochondrial Network ◽

Female Mice ◽

Mitochondrial Functions ◽

Store Operated Calcium Entry

Dynamic regulation of the mitochondrial network by mitofusins (MFNs) modulates energy production, cell survival, and many intracellular signaling events, including calcium handling. However, the relative importance of specific mitochondrial functions and their dependence on MFNs vary greatly among cell types. Osteoclasts have many mitochondria, and increased mitochondrial biogenesis and oxidative phosphorylation enhance bone resorption, but little is known about the mitochondrial network or MFNs in osteoclasts. Because expression of each MFN isoform increases with osteoclastogenesis, we conditionally deleted MFN1 and MFN2 (double conditional KO (dcKO)) in murine osteoclast precursors, finding that this increased bone mass in young female mice and abolished osteoclast precursor differentiation into mature osteoclasts in vitro. Defective osteoclastogenesis was reversed by overexpression of MFN2 but not MFN1; therefore, we generated mice lacking only MFN2 in osteoclasts. MFN2-deficient female mice had increased bone mass at 1 year and resistance to Receptor Activator of NF-κB Ligand (RANKL)-induced osteolysis at 8 weeks. To explore whether MFN-mediated tethering or mitophagy is important for osteoclastogenesis, we overexpressed MFN2 variants defective in either function in dcKO precursors and found that, although mitophagy was dispensable for differentiation, tethering was required. Because the master osteoclastogenic transcriptional regulator nuclear factor of activated T cells 1 (NFATc1) is calcium-regulated, we assessed calcium release from the endoplasmic reticulum and store-operated calcium entry and found that the latter was blunted in dcKO cells. Restored osteoclast differentiation by expression of intact MFN2 or the mitophagy-defective variant was associated with normalization of store-operated calcium entry and NFATc1 levels, indicating that MFN2 controls mitochondrion–endoplasmic reticulum tethering in osteoclasts.

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Administration of Saccharin to Neonatal Mice Influences Body Composition of Adult Males and Reduces Body Weight of Females

Endocrinology ◽

10.1210/en.2013-1995 ◽

2014 ◽

Vol 155 (4) ◽

pp. 1313-1326 ◽

Cited By ~ 12

Author(s):

Sebastian D. Parlee ◽

Becky R. Simon ◽

Erica L. Scheller ◽

Emilyn U. Alejandro ◽

Brian S. Learman ◽

...

Keyword(s):

Body Composition ◽

Body Weight ◽

Bone Mass ◽

Composition Analysis ◽

Male Body ◽

Adult Males ◽

Male Mice ◽

Female Mice ◽

Trabecular Bone Mass ◽

High Concentrations

Nutritional or pharmacological perturbations during perinatal growth can cause persistent effects on the function of white adipose tissue, altering susceptibility to obesity later in life. Previous studies have established that saccharin, a nonnutritive sweetener, inhibits lipolysis in mature adipocytes and stimulates adipogenesis. Thus, the current study tested whether neonatal exposure to saccharin via maternal lactation increased susceptibility of mice to diet-induced obesity. Saccharin decreased body weight of female mice beginning postnatal week 3. Decreased liver weights on week 14 corroborated this diminished body weight. Initially, saccharin also reduced male mouse body weight. By week 5, weights transiently rebounded above controls, and by week 14, male body weights did not differ. Body composition analysis revealed that saccharin increased lean and decreased fat mass of male mice, the latter due to decreased adipocyte size and epididymal, perirenal, and sc adipose weights. A mild improvement in glucose tolerance without a change in insulin sensitivity or secretion aligned with this leaner phenotype. Interestingly, microcomputed tomography analysis indicated that saccharin also increased cortical and trabecular bone mass of male mice and modified cortical bone alone in female mice. A modest increase in circulating testosterone may contribute to the leaner phenotype in male mice. Accordingly, the current study established a developmental period in which saccharin at high concentrations reduces adiposity and increases lean and bone mass in male mice while decreasing generalized growth in female mice.

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Osteoblast-specific overexpression of human interleukin-7 rescues the bone mass phenotype of interleukin-7-deficient female mice

Journal of Bone and Mineral Research ◽

10.1002/jbmr.1553 ◽

2012 ◽

Vol 27 (5) ◽

pp. 1030-1042 ◽

Cited By ~ 33

Author(s):

Hector L Aguila ◽

Se Hwan Mun ◽

Judith Kalinowski ◽

Douglas J Adams ◽

Joseph A Lorenzo ◽

...

Keyword(s):

Bone Mass ◽

Female Mice ◽

Interleukin 7

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Chronic Stimulation of Arcuate Kiss1 Neurons Decreases Bone Mass in Female Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.471 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A232-A232

Author(s):

Ruben Rodriguez ◽

Candice B Herber ◽

William C Krause ◽

Holly A Ingraham

Keyword(s):

Bone Mass ◽

Home Cage ◽

Designer Drugs ◽

Reproductive Capacity ◽

Estrogen Signaling ◽

Female Mice ◽

Cage Activity ◽

Increased Risk ◽

Chronic Activation ◽

Home Cage Activity

Abstract Loss of peripheral estrogen in postmenopausal women is often associated with decreased physical activity and loss of bone mass, leading to an increased risk of metabolic diseases, osteoporosis, and skeletal fragility. While it is well-established that loss of peripheral estrogen signaling results in bone loss, we previously found that eliminating central estrogen signaling paradoxically results in an unexpected massive increase in bone mass only in female mice. Specifically, deletion of estrogen receptor alpha (ERα) signaling in kisspeptin 1 (Kiss1) expressing neurons of the arcuate nucleus (ARCKiss1) increases bone mass at the expense of reproduction in female mice. Currently, the mechanisms and the neurocircuits that modulate these unexpected responses are unknown. Here, to begin addressing these questions, we asked if changing the neuronal output of ARCKiss1 neurons using chemogenetic manipulation of ARCKiss1 neurons might also alter bone mass and locomotion in female mice. To do this, we delivered stimulatory (AAV2-hM3Dq-mCherry) designer receptors exclusively activated by designer drugs (DREADDs) to the ARC of wild type and Kiss1-Cre+ (Kiss1-CrehM3q-DREADDs) female mice and asked if chronic activation of ARCKiss1 neurons might alter bone mass as analyzed by standard ex-vivo µCT imaging. Clozapine N-oxide (CNO) was delivered for 22 days (0.1 mg/mL). We also leveraged the ANY-Maze system to assess home cage activity over an extensive 96-hour period. Acute activation of ARCKiss1 tended to decrease home cage activity by nearly 40% in Kiss1-CrehM3q-DREADDs mice during the dark period compared to WT females. Interestingly, chronic activation of ARCKiss1 neurons significantly lowered trabecular bone volume by nearly 30%. Current studies are underway to ask if inhibiting ARCKiss1 neurons results in increased bone mass. Our findings collectively suggest that the neuronal activity of ARCKiss1 neurons is sufficient to shift energy allocation away from locomotion and bone-building to maximize reproductive capacity. We speculate that the widely used SERM in breast cancer treatment, Tamoxifen, might exert its bone sparing effect by silencing ARCKiss1 neurons.

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