scholarly journals Interaction among Calcium Diet Content, PTH (1-34) Treatment and Balance of Bone Homeostasis in Rat Model: The Trabecular Bone as Keystone

2019 ◽  
Vol 20 (3) ◽  
pp. 753 ◽  
Author(s):  
Marzia Ferretti ◽  
Francesco Cavani ◽  
Laura Roli ◽  
Marta Checchi ◽  
Maria Magarò ◽  
...  
Keyword(s):  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Rat Model ◽  
Calcium Content ◽  
Immunohistochemical Analysis ◽  
Normal Diet ◽  
Bone Homeostasis ◽  
Skeletal Homeostasis ◽  
Vertebral Bodies

The present study is the second step (concerning normal diet restoration) of the our previous study (concerning the calcium-free diet) to determine whether normal diet restoration, with/without concomitant PTH (1-34) administration, can influence amounts and deposition sites of the total bone mass. Histomorphometric evaluations and immunohistochemical analysis for Sclerostin expression were conducted on the vertebral bodies and femurs in the rat model. The final goals are (i) to define timing and manners of bone mass changes when calcium is restored to the diet, (ii) to analyze the different involvement of the two bony architectures having different metabolism (i.e., trabecular versus cortical bone), and (iii) to verify the eventual role of PTH (1-34) administration. Results evidenced the greater involvement of the trabecular bone with respect to the cortical bone, in response to different levels of calcium content in the diet, and the effect of PTH, mostly in the recovery of trabecular bony architecture. The main findings emerged from the present study are (i) the importance of the interplay between mineral homeostasis and skeletal homeostasis in modulating and guiding bone’s response to dietary/metabolic alterations and (ii) the evidence that the more involved bony architecture is the trabecular bone, the most susceptible to the dynamical balance of the two homeostases.

scholarly journals Interplay among calcium diet content, PTH(1-34) treatment and balance of bone homeostases in rat model: the trabecular bone as keystone

2019 ◽  
Author(s):  
Marzia Ferretti ◽  
Francesco Cavani ◽  
Laura Roli ◽  
Marta Checchi ◽  
Maria Sara Magarò ◽  
...  
Keyword(s):  
Bone Mass ◽  
Trabecular Bone ◽  
Rat Model ◽  
Immunohistochemical Analysis ◽  
Normal Diet ◽  
Second Step ◽  
Calcium Diet ◽  
Skeletal Homeostasis ◽  
Vertebral Bodies

The present study is the second step (concerning the normal-diet restoration) of the our previous one (concerning the calcium-free diet) to determine whether the normal-diet restoration, with/without concomitant PTH(1-34) administration, can influence amounts and deposition sites of the total bone mass. Histomorphometric evaluations and immunohistochemical analysis for Sclerostin expression were conducted on the vertebral bodies and femurs  in rat model. The final goals are: i) to define timing and manners of bone mass changes when calcium is restored in the diet; ii) to analyze the different involvement of the two bony architectures having different metabolism (i.e. trabecular versus cortical bone); iii) to verify the eventual role of PTH(1-34) administration. Results evidenced the greater involvement of the trabecular bone with respect to the cortical one, in answering to different calcium diet content, and the effect of PTH mostly in the recovery of trabecular bony architecture. The main findings emerged from the present study are: i) the importance of the interplay between mineral homeostasis and skeletal homeostasis in modulating and guiding bone answers to dietary/metabolic alterations and ii) the evidence that the more involved bony architecture is the trabecular one, the most susceptible to the dynamical balance of the two homeostases.

scholarly journals Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

2018 ◽  
Vol 238 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Thomas Funck-Brentano ◽  
Karin H Nilsson ◽  
Robert Brommage ◽  
Petra Henning ◽  
Ulf H Lerner ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bending Test ◽  
Bone Homeostasis ◽  
Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

scholarly journals Osteocyte- and late Osteoblast-derived NOTUM Reduces Cortical Bone Mass in Mice

2021 ◽  
Author(s):  
Karin H. Nilsson ◽  
Petra Henning ◽  
Maha El Shahawy ◽  
Jianyao Wu ◽  
Antti Koskela ◽  
...  
Keyword(s):  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Vertebral Fractures ◽  
Volume Fraction ◽  
Substantial Reduction ◽  
Lumbar Vertebrae ◽  
Bone Homeostasis ◽  
Increased Risk ◽  
Cortical Bone Mass

Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular bone, whereas the effect on non-vertebral fractures, mainly dependent on cortical bone, is less pronounced. WNT signaling is a crucial regulator of bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the cortical but not the trabecular bone mass. The aim of the present study was to determine if NOTUM increasing cortical bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in cortical bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1 expressing osteocytes and late osteoblasts (Dmp1-creNotumflox/flox mice). We observed that the Dmp1-creNotumflox/flox mice displayed a substantial reduction of Notum mRNA in cortical bone, resulting in increased cortical bone mass and decreased cortical porosity in femur, but no change in trabecular bone volume fraction (BV/TV) in femur or in the lumbar vertebrae L5 in Dmp1-creNotumflox/flox mice as compared to control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in cortical bone, and NOTUM derived from osteocytes/late osteoblasts reduces cortical bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase cortical bone mass and reduce non-vertebral fracture risk.

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

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.

Different responses of trabecular and cortical bone to 1,25(OH)2D3 infusion

1990 ◽  
Vol 259 (5) ◽  
pp. E715-E722
Author(s):  
D. D. Bikle ◽  
B. P. Halloran ◽  
C. McGalliard-Cone ◽  
E. Morey-Holton
Keyword(s):  
Bone Resorption ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Particle Distribution ◽  
Proximal Tibia ◽  
Bone Maturation ◽  
Dihydroxyvitamin D3 ◽  
Per Se ◽  
Bone Particles

Previous studies regarding the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on bone have suggested that 1,25(OH)2D3 increases bone mass and calcium. Many of these studies have focused on trabecular or total bone without examining cortical bone per se. To determine whether the response of trabecular bone to 1,25(OH)2D3 differed from the response of cortical bone, we infused 1,25(OH)2D3 into rats and examined bone mass, 45Ca accumulation, and the density distribution of bone particles (as a measure of bone maturation) in both the proximal tibia and shaft. In the proximal tibia 1,25(OH)2D3 decreased 45Ca accumulation, yet increased bone mass and shifted the particle distribution to more mineralized fractions. In the shaft there was a redistribution of bone to less mineralized fractions that was not accompanied by a change in total bone mass or a decrease in 45Ca accumulation. Thus 1,25(OH)2D3 may retard bone maturation and mineralization throughout the tibia, but this effect in the proximal tibia appears to be overshadowed by a reduction in bone resorption resulting in an accumulation of well-mineralized bone in that region. Bone resorption, however, was not measured directly. The net result is an increase in bone mass and density of trabecular bone not seen in cortical bone.

scholarly journals The bone-sparing effects of estrogen and WNT16 are independent of each other

2015 ◽  
Vol 112 (48) ◽  
pp. 14972-14977 ◽  
Author(s):  
Sofia Movérare-Skrtic ◽  
Jianyao Wu ◽  
Petra Henning ◽  
Karin L. Gustafsson ◽  
Klara Sjögren ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Integration Site ◽  
Mineral Density ◽  
Trabecular Bone Mass ◽  
Sparing Effect ◽  
Total Body ◽  
Cortical Bone Mass

Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16−/− mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females is WNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl-Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl-Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16−/− mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16−/− and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16-targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.

scholarly journals Effects of Estrogen with Micronized Progesterone on Cortical and Trabecular Bone Mass and Microstructure in Recently Postmenopausal Women

2013 ◽  
Vol 98 (2) ◽  
pp. E249-E257 ◽  
Author(s):  
Joshua N. Farr ◽  
Sundeep Khosla ◽  
Yuko Miyabara ◽  
Virginia M. Miller ◽  
Ann E. Kearns
Keyword(s):  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Distal Radius ◽  
Thoracic Spine ◽  
Quantitative Computed Tomography ◽  
Volumetric Bone Mineral Density ◽  
Mineral Density ◽  
Trabecular Microarchitecture ◽  
Micronized Progesterone

Abstract Context: In women, cortical bone mass decreases significantly at menopause. By contrast, loss of trabecular bone begins in the third decade and accelerates after menopause. Objective: The aim of the study was to investigate the effects of estrogen on cortical and trabecular bone. Design: The Kronos Early Estrogen Prevention Study is a double-blind, randomized, placebo-controlled trial of menopausal hormone treatment (MHT) in women, enrolled within 6–36 months of their final menstrual period. Setting: The study was conducted at the Mayo Clinic, Rochester, Minnesota. Intervention: Subjects were treated with placebo (n = 31), or .45 mg/d conjugated equine estrogens (n = 20), or transdermal 50 μg/d 17β-estradiol (n = 25) with pulsed micronized progesterone. Main Outcome Measures: Cortical and trabecular microarchitecture at the distal radius was assessed by high-resolution peripheral quantitative computed tomography. Results: At the distal radius, cortical volumetric bone mineral density (vBMD) decreased, and cortical porosity increased in the placebo group; MHT prevented these changes. By contrast, MHT did not prevent decreases in trabecular microarchitecture at the radius. However, MHT prevented decreases in trabecular vBMD at the thoracic spine (assessed in a subset of subjects; n = 51). These results indicate that MHT prevents deterioration in radial cortical vBMD and porosity in recently menopausal women. Conclusion: The maintenance of cortical bone in response to estrogen likely has important clinical implications because cortical bone morphology plays an important role in bone strength. However, effects of MHT on trabecular bone at the radius differ from those at the thoracic spine. Underlying mechanisms for these site-specific effects of MHT on cortical vs trabecular bone require further investigation.

Effect of Oophorectomy and Calcium Deprivation on Bone Mass in the Rat

1978 ◽  
Vol 54 (4) ◽  
pp. 439-446 ◽  
Author(s):  
A. Hodgkinson ◽  
Jean E. Aaron ◽  
A. Horsman ◽  
M. S. F. McLachlan ◽  
B. E. C. Nordin
Keyword(s):  
Bone Mass ◽  
Trabecular Bone ◽  
Dry Weight ◽  
Calcium Deficiency ◽  
Normal Diet ◽  
Female Rats ◽  
Cross Sectional ◽  
Calcium Diet ◽  
Low Calcium Diet ◽  
Low Calcium

1. The effects of a low calcium diet and of oophorectomy, separately and together, on cortical and trabecular bone mass, have been examined in mature female rats. 2. Calcium deprivation caused a significant decrease of weight, cortical cross-sectional area and ratio of cortical to total area in the femur, it significantly reduced the volume of trabecular bone and increased the percentage of osteoid surface in the tail vertebrae, and in addition increased the urinary excretion of phosphate and, initially, of hydroxyproline. 3. Oophorectomy caused similar though smaller changes in trabecular bone and urine, whereas the effects of oophorectomy on cortical bone were greater on a low calcium intake than on a normal intake. 4. The ash weight of the femora, expressed as a percentage of the total dry weight, was unaffected by calcium deprivation or oophorectomy alone but was significantly reduced when the two occurred together. 5. The percentage of resorption surfaces in the vertebrae tended to increase on the low calcium diet and after oophorectomy on the normal diet but decreased after oophorectomy on a low calcium diet. 6. It is concluded that oophorectomy and calcium deficiency each reduce bone mass in the adult rat but the greatest effect is seen when they are combined.

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