Sex-related differences in the skeletal phenotype of aged vitamin D receptor global knockout mice

Ryan, Jackson W.; Starczak, Yolandi; Tsangari, Helen; Sawyer, Rebecca; Davey, Rachel A; Atkins, Gerald J.; Morris, Howard A.; Anderson, Paul

doi:10.1016/j.jsbmb.2015.12.005

Cited by 14 publications

(9 citation statements)

References 34 publications

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“…This finding is in agreement with normal values for serum Ca and phosphorus and only slightly elevated PTH levels in four-month-old VDR ∆/∆ mice on the RD [9], and it is also in line with previous observations of VDR knockout mice fed with the rescue diet [14]. The RD prevented the development of osteomalacia in other VDR knockout mice [19], and, moreover, no signs of osteomalacia were observed previously in our RD-fed VDR ∆/∆ mice at the baseline [9], which was confirmed in the current study by the absence of enhanced amounts of unmineralized bone matrix, as visualized by inverted qBEI imaging. Taken together, these findings suggest that the RD is able to maintain a normal bone phenotype in adult VDR ∆/∆ mice.…”

Section: Discussionsupporting

confidence: 92%

No Role of Osteocytic Osteolysis in the Development and Recovery of the Bone Phenotype Induced by Severe Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice

Misof

Blouin

Hofstaetter

et al. 2020

IJMS

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Osteocytic osteolysis/perilacunar remodeling is thought to contribute to the maintenance of mineral homeostasis. Here, we utilized a reversible, adult-onset model of secondary hyperparathyroidism to study femoral bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging. Male mice with a non-functioning vitamin D receptor (VDRΔ/Δ) or wild-type mice were exposed to a rescue diet (RD) (baseline) and subsequently to a low calcium challenge diet (CD). Thereafter, VDRΔ/Δ mice received either the CD, a normal diet (ND), or the RD. At baseline, BMDD and OLS characteristics were similar in VDRΔ/Δ and wild-type mice. The CD induced large cortical pores, osteomalacia, and a reduced epiphyseal average degree of mineralization in the VDRΔ/Δ mice relative to the baseline (−9.5%, p < 0.05 after two months and −10.3%, p < 0.01 after five months of the CD). Switching VDRΔ/Δ mice on the CD back to the RD fully restored BMDD to baseline values. However, OLS remained unchanged in all groups of mice, independent of diet. We conclude that adult VDRΔ/Δ animals on an RD lack any skeletal abnormalities, suggesting that VDR signaling is dispensable for normal bone mineralization as long as mineral homeostasis is normal. Our findings also indicate that VDRΔ/Δ mice attempt to correct a calcium challenge by enhanced osteoclastic resorption rather than by osteocytic osteolysis.

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Section: Discussionsupporting

confidence: 92%

No Role of Osteocytic Osteolysis in the Development and Recovery of the Bone Phenotype Induced by Severe Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice

Misof

Blouin

Hofstaetter

et al. 2020

IJMS

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“…The VDR knockout mice have exhibited significant gonadal insufficiency, decreased sperm count and motility [51, 53]. Sex difference in the skeletal phenotype was also displayed in male mice lacking VDR gene [54]. Also, the low vitamin D status is associated with increased diabetes risk in hypo gonadal men [55].…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Status, Gender Differences, and Cardiometabolic Health Disparities

et al. 2017

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Background: Vitamin D deficiency is an unrecognized epidemic found in India and also worldwide. Despite the high prevalence of diabetes among Indians, there is a paucity of data showing the relationship between vitamin D status and cardiometabolic disparities. In this study, we have examined the relationship between vitamin D and cardiometabolic traits in a population from India. Methods: Circulating 25(OH)D levels were measured in 3,879 participants from the Asian Indian Diabetic Heart Study using ELISA kits. Results: Vitamin D levels were significantly reduced (p < 0.0001) in both men and women with obesity. However, compared to women, serum vitamin D was consistently lower in men (p < 0.02), irrespective of the presence of obesity and type 2 diabetes. Multivariate regression revealed strong interaction of vitamin D with body mass index that resulted in increased fasting glucose (p = 0.001) and reduced homeostasis model assessment of β-cell function (HOMA-B; p = 0.01) in normoglycemic individuals. However, in gender-stratified analysis, this association was restricted to men for both fasting glucose (p = 2.4 × 10^-4) and HOMA-B (p = 0.001). Conclusions: Our findings suggest that vitamin D deficiency may significantly enhance the risk of cardiometabolic disease among Asian Indians. Future randomized trials and genetic studies are expected to clarify the underlying mechanisms for gender differences in vitamin D deficiency, and whether vitamin D-driven improvement in testosterone may contribute to beneficial cardiometabolic outcomes in men.

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“…Gender disparity in fracture risk stems from differences in peak bone mass accrual, bone size, and geometry (50) . Sex steroids that essentially drive skeletal variations in men and women integrate systemic cues such as that from vitamin D, IGF/GH, and PTH to dictate dimorphism at the cellular level (19,(51)(52)(53) .…”

Section: Discussionmentioning

confidence: 99%

TGFβ regulation of perilacunar/canalicular remodeling is sexually dimorphic

Dole

Yee

Mazur

et al. 2019

Preprint

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1.AbstractBone fragility is the product of defects in bone mass and bone quality, both of which show sex-specific differences. Despite this, the cellular and molecular mechanisms underpinning the sexually dimorphic control of bone quality remain unclear, limiting our ability to effectively prevent fractures, especially in postmenopausal osteoporosis. Recently, using male mice, we found that systemic or osteocyte-intrinsic inhibition of TGFβ signaling, achieved using the 9.6-kb DMP1 promoter-driven Cre recombinase (TβRIIocy−/− mice), suppresses osteocyte perilacunar/canalicular remodeling (PLR) and compromises bone quality. Since systemic TGFβ inhibition more robustly increases bone mass in female than male mice, we postulated that sex-specific differences in bone quality could likewise result, in part, from dimorphic regulation of PLR by TGFβ. Moreover, since lactation induces PLR, we examined the effect of TGFβ inhibition on the female skeleton during lactation. In contrast to males, female mice that possess an osteocyte-intrinsic defect in TGFβ signaling were protected from TGFβ-dependent defects in PLR and bone quality. The expression of requisite PLR enzymes, the lacuno-canalicular network, and the flexural strength of female TβRIIocy−/− bone was intact. With lactation, however, bone loss, and induction in PLR and osteocytic parathyroid hormone type I receptor (PTHR1) expression, were suppressed in TβRIIocy−/− bone, relative to wild-type. Indeed, differential control of PTHR1 expression, by TGFβ and other factors, may contribute to dimorphism in PLR regulation in male and female TβRIIocy−/− mice. These findings provide key insights into the sex-based differences in osteocyte PLR that underlie bone quality and highlight TGFβ signaling as a crucial regulator of lactation-induced PLR.

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Sex-related differences in the skeletal phenotype of aged vitamin D receptor global knockout mice

Cited by 14 publications

References 34 publications

No Role of Osteocytic Osteolysis in the Development and Recovery of the Bone Phenotype Induced by Severe Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice

No Role of Osteocytic Osteolysis in the Development and Recovery of the Bone Phenotype Induced by Severe Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice

Vitamin D Status, Gender Differences, and Cardiometabolic Health Disparities

TGFβ regulation of perilacunar/canalicular remodeling is sexually dimorphic

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