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 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 Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats

2011 ◽  
Vol 212 (2) ◽  
pp. 179-186 ◽  
Author(s):  
Rana Samadfam ◽  
Malaika Awori ◽  
Agnes Bénardeau ◽  
Frieder Bauss ◽  
Elena Sebokova ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Bone Mineral ◽  
Combination Treatment ◽  
Mass Gain ◽  
Ovariectomized Rats ◽  
Concomitant Treatment ◽  
Mineral Density ◽  
Ovx Rats

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.

scholarly journals Osteopontin Deficiency Induces Parathyroid Hormone Enhancement of Cortical Bone Formation

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 2132-2140 ◽  
Author(s):  
Keiichiro Kitahara ◽  
Muneaki Ishijima ◽  
Susan R. Rittling ◽  
Kunikazu Tsuji ◽  
Hisashi Kurosawa ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Formation ◽  
Bone Mass ◽  
Cortical Bone ◽  
Cancellous Bone ◽  
Wild Type ◽  
Mineral Density ◽  
Cortical Bone Mass ◽  
Intermittent Pth

Intermittent PTH treatment increases cancellous bone mass in osteoporosis patients; however, it reveals diverse effects on cortical bone mass. Underlying molecular mechanisms for anabolic PTH actions are largely unknown. Because PTH regulates expression of osteopontin (OPN) in osteoblasts, OPN could be one of the targets of PTH in bone. Therefore, we examined the role of OPN in the PTH actions in bone. Intermittent PTH treatment neither altered whole long-bone bone mineral density nor changed cortical bone mass in wild-type 129 mice, although it enhanced cancellous bone volume as reported previously. In contrast, OPN deficiency induced PTH enhancement of whole-bone bone mineral density as well as cortical bone mass. Strikingly, although PTH suppressed periosteal bone formation rate (BFR) and mineral apposition rate (MAR) in cortical bone in wild type, OPN deficiency induced PTH activation of periosteal BFR and MAR. In cancellous bone, OPN deficiency further enhanced PTH increase in BFR and MAR. Analysis on the cellular bases for these phenomena indicated that OPN deficiency augmented PTH enhancement in the increase in mineralized nodule formation in vitro. OPN deficiency did not alter the levels of PTH enhancement of the excretion of deoxypyridinoline in urine, the osteoclast number in vivo, and tartrate-resistant acid phosphatase-positive cell development in vitro. These observations indicated that OPN deficiency specifically induces PTH activation of periosteal bone formation in the cortical bone envelope.

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.

Calcitriol corrects bone loss induced by oophorectomy in rats

1986 ◽  
Vol 250 (1) ◽  
pp. E35-E38
Author(s):  
M. C. Faugere ◽  
S. Okamoto ◽  
H. F. DeLuca ◽  
H. H. Malluche
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Cortical Bone ◽  
Structure Formation ◽  
Bone Structure ◽  
Subcutaneous Injections ◽  
Calcium And Phosphorus ◽  
Cortical Bone Mass ◽  
Osteoid Seam ◽  
Plate Width

The effects of calcitriol on histomorphometric parameters of bone structure, formation, and resorption were evaluated in 21 normal or oophorectomized rats. Twelve rats were oophorectomized; six of these received daily subcutaneous injections of 135 pmol of calcitriol for 14 wk starting 38 wk after oophorectomy. Nine rats were sham operated; five of these received the same treatment with calcitriol. There were no differences in serum calcium and phosphorus between sham-operated and oophorectomized animals and rats with or without calcitriol. Calcitriol treatment of sham-operated rats produced an increase in cancellous and cortical bone mass. Oophorectomy resulted in decreased cancellous and cortical bone mass and in a decreased ratio between mineralized and nonmineralized bone. There was no difference in bone-osteoclast interface and osteoid seam width among all groups of rats. Calcitriol corrected, at least in part, the bone loss in oophorectomized animals, normalized the ratio between mineralized and nonmineralized bone, and restored mean growth plate width to normal.

scholarly journals Fat Mass Exerts a Greater Effect on Cortical Bone Mass in Girls than Boys

2010 ◽  
Vol 95 (2) ◽  
pp. 699-706 ◽  
Author(s):  
Adrian Sayers ◽  
Jonathan H. Tobias
Keyword(s):  
Bone Mineral Density ◽  
Bone Mass ◽  
Cortical Bone ◽  
Bone Mineral ◽  
Fat Mass ◽  
Quantitative Computed Tomography ◽  
Positive Association ◽  
Mineral Density ◽  
Cortical Bone Mineral Density ◽  
Cortical Bone Mass

Abstract Context: It is unclear whether fat mass (FM) and lean mass (LM) differ in the way they influence cortical bone development in boys and girls. Objective: The aim of the study was to investigate the contributions of total body FM and LM to parameters related to cortical bone mass and geometry. Design/Setting: We conducted a longitudinal birth cohort study, the Avon Longitudinal Study of Parents and Children. Participants: A total of 4005 boys and girls (mean age, 15.5 yr) participated in the study. Outcome Measures: We measured cortical bone mass, cortical bone mineral content (BMCC), cortical bone mineral density, periosteal circumference (PC), and endosteal circumference by tibial peripheral quantitative computed tomography. Results: LM had a similar positive association with BMCC in boys and girls [regression coefficients with 95% confidence interval (CI); P for gender interactions: boys/girls, 0.952 (0.908, 0.997); P = 0.85]. However, the mechanisms by which LM influenced bone mass differed according to gender because LM was positively associated with PC more strongly in girls [boys, 0.579 (0.522, 0.635); girls, 0.799 (0.722, 0.875); P &lt; 0.0001], but was only associated with cortical bone mineral density in boys [boys, 0.443 (0.382, 0.505); girls, 0.014 (−0.070, 0.097); P &lt; 0.0001]. There was a stronger positive association between FM and BMCC in girls [boys, 0.227 (0.185, 0.269); girls, 0.355 (0.319, 0.392); P &lt; 0.0001]. This reflected both a greater positive association of FM with PC in girls [boys, 0.213 (0.174, 0.253); girls, 0.312 (0.278, 0.347); P = 0.0002], and a stronger negative association with endosteal circumferencePC [boys, −0.059 (−0.096, 0.021); girls, −0.181 (−0.215, −0.146); P &lt; 0.0001]. Conclusions: Whereas LM stimulates the accrual of cortical bone mass to a similar extent in boys and girls, FM is a stronger stimulus for accrual of cortical bone mass in girls, reflecting a greater tendency in females for FM to stimulate periosteal growth and suppress endosteal expansion.

Effect of diet-induced weight loss on total body bone mass

1992 ◽  
Vol 82 (4) ◽  
pp. 429-432 ◽  
Author(s):  
J. E. Compston ◽  
M. A. Laskey ◽  
P. I. Croucher ◽  
A. Coxon ◽  
S. Kreitzman
Keyword(s):  
Bone Mineral Density ◽  
Weight Loss ◽  
Bone Loss ◽  
Bone Mass ◽  
Bone Mineral ◽  
Areal Bone Mineral Density ◽  
Mineral Density ◽  
Total Body ◽  
Total Body Bone Mineral ◽  
Body Bone

1. Total body areal bone mineral density was measured by dual-energy X-ray absorptiometry in eight women before and 10 weeks after a very-low-calorie diet [405 kcal (1701 kJ)/day]. 2. The mean weight loss of 15.6 kg was accompanied by a statistically significant reduction in total body bone mineral density from 1.205 ± 0.056 to 1.175 ± 0.058 g/cm2 (mean ± sd, P < 0.005). 3. After cessation of the diet, weight gradually increased and by 10 months was similar to baseline values. Total body bone mineral density also increased after stopping the diet and mean values obtained 10 months after the diet did not differ significantly from initial values. Throughout the study total body bone mineral density values in all subjects were well within the range reported for normal subjects. 4. These data indicate that diet-induced weight loss is associated with rapid bone loss, subsequent weight gain being accompanied by increases in bone mass. Further studies are required to establish the clinical significance of these findings and, in particular, the skeletal distribution of bone loss.

scholarly journals Osteoblast‐derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans

2019 ◽  
Vol 33 (10) ◽  
pp. 11163-11179 ◽  
Author(s):  
Sofia Movérare-Skrtic ◽  
Karin H. Nilsson ◽  
Petra Henning ◽  
Thomas Funck-Brentano ◽  
Maria Nethander ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mass ◽  
Cortical Bone ◽  
Bone Mineral ◽  
Mineral Density ◽  
Cortical Bone Mass

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.

Sign in / Sign up

Export Citation Format

Share Document