The Murine Osteoclasts Lacking Transferrin Receptor 1 have Altered Mitochondrial Metabolism, Cytoskeletal Organization and Increased Trabecular Bone Mass

Increased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation and bone-resorbing activities. Transferrin receptor 1 (TFR1) mediates cellular iron uptake through endocytosis of iron-loaded transferrin and its expression increases during osteoclast differentiation. Nonetheless, the precise functions of TFR1 and TFR1-mediated iron uptake in osteoclast biology and skeletal homeostasis remain incompletely understood. To investigate the role of TFR1 in osteoclast lineage cells, we conditionally deleted Tfr1 gene in myeloid precursors or mature osteoclasts by crossing Tfr1-floxed mice with LysM-Cre and Ctsk-Cre mice, respectively. Skeletal phenotyping by μCT and histology unveiled that loss of Tfr1 in osteoclast progenitor cells resulted in a three-fold increase in trabecular bone mass in the long bones of 10-week old female but not male mice. Although high trabecular bone volume in long bones was seen in both male and female mice with deletion of Tfr1 in mature osteoclasts, this phenotype was more pronounced in female knockout mice. Mechanistically, disruption of Tfr1 expression attenuated mitochondrial metabolism and cytoskeletal organization in mature osteoclasts, leading to decreased bone resorption with no impact on osteoclastogenesis. These results indicate that Tfr1-mediated iron uptake is specifically required for osteoclast function and is indispensable for bone remodeling.

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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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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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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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