A novel mechanical parameter to quantify the microarchitecture effect on apparent modulus of trabecular bone: A computational analysis of ineffective bone mass

Peroxisome proliferator-activated receptor (PPAR) γ agonists, such as pioglitazone (Pio), improve glycemia and lipid profile but are associated with bone loss and fracture risk. Data regarding bone effects of PPARα agonists (including fenofibrate (Feno)) are limited, although animal studies suggest that Feno may increase bone mass. This study investigated the effects of a 13-week oral combination treatment with Pio (10 mg/kg per day)+Feno (25 mg/kg per day) on body composition and bone mass parameters compared with Pio or Feno alone in adult ovariectomized (OVX) rats, with a 4-week bone depletion period, followed by a 6-week treatment-free period. Treatment of OVX rats with Pio+Feno resulted in ∼50% lower fat mass gain compared with Pio treatment alone. Combination treatment with Pio+Feno partially prevented Pio-induced loss of bone mineral content (∼45%) and bone mineral density (BMD; ∼60%) at the lumbar spine. Similar effects of treatments were observed at the femur, most notably at sites rich in trabecular bone. At the proximal tibial metaphysis, concomitant treatment with Pio+Feno prevented Pio exacerbation of ovariectomy-induced loss of trabecular bone, resulting in BMD values in the Pio+Feno group comparable to OVX controls. Discontinuation of Pio or Feno treatment of OVX rats was associated with partial reversal of effects on bone loss or bone mass gain, respectively, while values in the Pio+Feno group remained comparable to OVX controls. These data suggest that concurrent/dual agonism of PPARγ and PPARα may reduce the negative effects of PPARγ agonism on 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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Effects of sequential osteoporosis treatments on trabecular bone in adult rats with low bone mass

Osteoporosis International ◽

10.1007/s00198-014-2678-5 ◽

2014 ◽

Vol 25 (6) ◽

pp. 1735-1750 ◽

Cited By ~ 17

Author(s):

S. K. Amugongo ◽

W. Yao ◽

J. Jia ◽

Y.-A. E. Lay ◽

W. Dai ◽

...

Keyword(s):

Bone Mass ◽

Trabecular Bone ◽

Low Bone Mass ◽

Adult Rats

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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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Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells

Blood ◽

10.1182/blood-2011-06-360933 ◽

2012 ◽

Vol 119 (11) ◽

pp. 2489-2499 ◽

Cited By ~ 49

Author(s):

Laura M. Calvi ◽

Olga Bromberg ◽

Yumie Rhee ◽

Jonathan M. Weber ◽

Julianne N. P. Smith ◽

...

Keyword(s):

Stem Cells ◽

Parathyroid Hormone ◽

Bone Mass ◽

Hematopoietic Stem Cells ◽

Trabecular Bone ◽

Bone Matrix ◽

Osteoblastic Cells ◽

Hematopoietic Stem ◽

Parathyroid Hormone Receptor ◽

Mineralized Bone Matrix

Abstract Microenvironmental expansion of hematopoietic stem cells (HSCs) is induced by treatment with parathyroid hormone (PTH) or activation of the PTH receptor (PTH1R) in osteoblastic cells; however, the osteoblastic subset mediating this action of PTH is unknown. Osteocytes are terminally differentiated osteoblasts embedded in mineralized bone matrix but are connected with the BM. Activation of PTH1R in osteocytes increases osteoblastic number and bone mass. To establish whether osteocyte-mediated PTH1R signaling expands HSCs, we studied mice expressing a constitutively active PTH1R in osteocytes (TG mice). Osteoblasts, osteoclasts, and trabecular bone were increased in TG mice without changes in BM phenotypic HSCs or HSC function. TG mice had progressively increased trabecular bone but decreased HSC function. In severely affected TG mice, phenotypic HSCs were decreased in the BM but increased in the spleen. TG osteocytes had no increase in signals associated with microenvironmental HSC support, and the spindle-shaped osteoblastic cells that increased with PTH treatment were not present in TG bones. These findings demonstrate that activation of PTH1R signaling in osteocytes does not expand BM HSCs, which are instead decreased in TG mice. Therefore, osteocytes do not mediate the HSC expansion induced by PTH1R signaling. Further, osteoblastic expansion is not sufficient to increase HSCs.

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