Expressions 1992

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Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study.

BACKGROUND: Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. METHODS AND FINDINGS: We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. CONCLUSIONS: In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease

Short-term glucocorticoid excess blunts abaloparatide-induced increase in femoral bone mass and strength in mice

Abstract Glucocorticoids (GCs), such as prednisolone, are widely used to treat inflammatory diseases. Continuously long-term or high dose treatment with GCs is one of the most common causes of secondary osteoporosis and is associated with sarcopenia and increased risk of debilitating osteoporotic fragility fractures. Abaloparatide (ABL) is a potent parathyroid hormone-related peptide analog, which can increase bone mineral density (aBMD), improve trabecular microarchitecture, and increase bone strength. The present study aimed to investigate whether GC excess blunts the osteoanabolic effect of ABL. Sixty 12–13-week-old female RjOrl:SWISS mice were allocated to the following groups: Baseline, Control, ABL, GC, and GC + ABL. ABL was administered as subcutaneous injections (100 μg/kg), while GC was delivered by subcutaneous implantation of a 60-days slow-release prednisolone-pellet (10 mg). The study lasted four weeks. GC induced a substantial reduction in muscle mass, trabecular mineral apposition rate (MAR) and bone formation rate (BFR/BS), and endocortical MAR compared with Control, but did not alter the trabecular microarchitecture or bone strength. In mice not receiving GC, ABL increased aBMD, bone mineral content (BMC), cortical and trabecular microarchitecture, mineralizing surface (MS/BS), MAR, BFR/BS, and bone strength compared with Control. However, when administered concomitantly with GC, the osteoanabolic effect of ABL on BMC, cortical morphology, and cortical bone strength was blunted. In conclusion, at cortical bone sites, the osteoanabolic effect of ABL is generally blunted by short-term GC excess

The effect of oral dabigatran etexilate on bone density, strength, and microstructure in healthy mice

Thrombin is a key component in the coagulation cascade where it converts factor V, VIII, XI, and fibrinogen. In addition to the abundant production of thrombin in the liver, osteoclasts synthesize and secrete thrombin as well. Osteoblasts express thrombin receptors, and it has been reported that thrombin stimulates the expression of RANKL relatively to OPG, resulting in greater osteoclast activation and bone degradation. Pradaxa (dabigatran etexilate, DE) is a new anticoagulant, which has recently been approved for clinical use. DE is a direct thrombin inhibitor with potential to modulate the RANKL/OPG ratio and thereby limit osteoclast activation and bone degradation. The purpose of the study was to investigate whether DE can increase bone density, bone strength, and bone microstructure in healthy male and female mice and to investigate whether the effect of DE is sex-dependent. Twenty-eight 14-week-old male C57BL/6 mice were stratified by weight into 4 groups: 1. Control 3weeks; 2. DE 3weeks; 3. Control 6weeks; 4. DE 6weeks. An identical study design was applied to twenty-four 14-week-old female C57BL/6 mice. Chow mixed with DE was offered ad libitum, resulting in a dose of 1.70mgDE/g body weight and 1.52mgDE/g body weight, to female and male mice, respectively. The animals were euthanized after 3 or 6weeks. Bone mineral density (aBMD) and bone mineral content (BMC) were evaluated with DEXA, 3D microstructural properties were determined with μCT, bone strength was determined with mechanical testing, and bone formation and resorption was evaluated with bone histomorphometry. In female mice, DE resulted in significant higher tibial aBMD values after 6weeks of intervention. Furthermore, DE significantly increased tibial diaphyseal cortical bone area and tissue area, which was accompanied by significantly increased strength of the tibial shaft. DE had no effect on femoral cortical bone or on femoral and vertebral trabecular 3D microstructure. Finally, bone histomorphometry showed that DE had no effect on MS/BS or Oc.S/BS. In male mice, no bone positive effects of DE were found in any of the parameters investigated. In conclusion, intervention with DE may result in a weak positive site specific effect at tibial cortical bone in female mice, and importantly, no major deleterious effects of DE on bone tissue were seen in either female or male mice despite the relatively high dose of DE used. Keywords: Blood clotting, μCT, Dabigatran etexilate, Bone formatio

Activin type IIA decoy receptor and intermittent parathyroid hormone in combination overturns the bone loss in disuse-osteopenic mice

Damage of the lower motor neuron cell bodies or their axons results in reduced or abolished voluntary movement accompanied by a substantial loss of bone and muscle mass. Intermittent parathyroid hormone 1–34 (PTH) (teriparatide) is one of the most potent bone-anabolic treatment regimens. ActRIIA-mFc is an activin type IIA decoy receptor that increases bone mass mediated by inhibition of the activin receptor signaling pathway. We investigated whether PTH or ActRIIA-mFc alone or in combination could prevent loss of bone and muscle mass induced by injecting botulinum toxin A (BTX) into the right hind limb in mice. Seventy-two 16-week-old female C57BL/6 mice were allocated to the following groups: Baseline, Control, BTX, BTX + ActRIIA-mFc (10 mg/kg), BTX + PTH (100 μg/kg), and BTX + ActRIIA-mFc + PTH. The mice were sacrificed after three weeks of disuse and treatment. In contrast to monotherapy with PTH, ActRIIA-mFc alone or in combination with PTH was able partly or completely to prevent disuse-induced loss of whole femoral bone mass, trabecular thickness, and bone strength. Moreover, an additive effect of ActRIIA-mFc and PTH on areal bone mineral density and trabecular bone volume was found. In summary, ActRIIA-mFc and PTH in combination were more effective in preventing disuse-induced bone loss and deterioration of trabecular micro-architecture than either treatment alone