IU Indianapolis ScholarWorks :: Browsing by Subject "Vitamin D"

Browsing by Subject "Vitamin D"

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Calcitriol Regulates the Differentiation of IL-9-Secreting Th9 Cells by Modulating the Transcription Factor PU.1
(American Association of Immunologists, 2020-03-01) Vyas, Shachi Pranjal; Hansda, Arman Kunwar; Kaplan, Mark H.; Goswami, Ritobrata; Pediatrics, School of Medicine
Vitamin D can modulate the innate and adaptive immune system. Vitamin D deficiency has been associated with various autoimmune diseases. Th9 cells are implicated in the pathogenesis of numerous autoimmune diseases. Thus, we investigated the role of calcitriol (active metabolite of vitamin D) in the regulation of Th9 cell differentiation. In this study, we have unraveled the molecular mechanisms of calcitriol-mediated regulation of Th9 cell differentiation. Calcitriol significantly diminished IL-9 secretion from murine Th9 cells, associated with downregulated expression of the Th9-associated transcription factor, PU.1. Ectopic expression of VDR in Th9 cells attenuated the percentage of IL-9-secreting cells. VDR associated with PU.1 in Th9 cells. Using a series of mutations, we were able to dissect the VDR domain involved in the regulation of Il9 gene. The VDR-PU.1 interaction prevented the accessibility of PU.1 to the Il9 gene promoter thereby restricting its expression. However, the expression of Foxp3, Treg-specific transcription factor, was enhanced in the presence of calcitriol in Th9 cells. When Th9 cells are treated with both calcitriol and TSA (histone deacetylase inhibitor), the level of IL-9 reached to the level of wild-type untreated Th9 cells. Calcitriol attenuated specific histone acetylation at the Il9 gene. In contrast, calcitriol enhanced the recruitment of the histone modifier, HDAC1 at the Il9 gene promoter. In summary, we have identified that calcitriol blocked the access of PU.1 to Il9 gene by reducing its expression and associating with it as well as regulated the chromatin of Il9 gene to regulate expression.
Clinical utility of simultaneous quantitation of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by LC-MS/MS involving derivatization with DMEQ-TAD
(The Endocrine Society, 2014-07) Kaufmann, Martin; Gallagher, J. Christopher; Peacock, Munro; Schlingmann, Karl-Peter; Konrad, Martin; DeLuca, Hector F.; Sigueiro, Rita; Lopez, Borja; Mourino, Antonio; Maestro, Miguel; St-Arnaud, René; Finkelstein, Joel S.; Cooper, Donald P.; Jones, Glenville; Department of Medicine, IU School of Medicine
CONTEXT: The discovery of hypercalcemic diseases due to loss-of-function mutations in 25-hydroxyvitamin D-24-hydroxylase has placed a new demand for sensitive and precise assays for 24,25-dihydroxyvitamin D [24,25-(OH)2D]. OBJECTIVE: We describe a novel liquid chromatography and tandem mass spectrometry-based method involving derivatization with DMEQ-TAD {4-[2-(6,7-dimethoxy-4-methyl-3,4-dihydroquinoxalinyl)ethyl]-1,2,4-triazoline-3,5-dione} to simultaneously assay multiple vitamin D metabolites including 25-hydroxyvitamin D (25-OH-D) and 24,25-(OH)2D using 100 μL of serum with a 5-minute run time. DESIGN: The assay uses a newly synthesized internal standard d6-24,25-(OH)2D3 enabling the quantitation of 24,25-(OH)2D3 as well as the determination of the ratio of 25-OH-D3 to 24,25-(OH)2D3, a physiologically useful parameter. SETTING: We report data on more than 1000 normal and disease samples involving vitamin D deficiency or hypercalcemia in addition to studies involving knockout mouse models. RESULTS: The assay showed good correlation with samples from quality assurance schemes for 25-OH-D (25-OH-D2 and 25-OH-D3) determination (-2% to -5% bias) and exhibited low inter- and intraassay coefficients of variation (4%-7%) and lower limits of quantitation of 0.25-0.45 nmol/L. In clinical studies, we found a strong correlation between serum levels of 25-OH-D3 and 24,25-(OH)2D3 (r(2) = 0.80) in subjects over a broad range of 25-OH-D3 values and a marked lack of production of 24,25-(OH)2D3 below 25 nmol/L of 25-OH-D. The ratio of 25-OH-D3 to 24,25-(OH)2D3, which remained less than 25 in vitamin D-sufficient subjects (serum 25-OH-D < 50 nmol/L) but was greatly elevated (80-100) in patients with idiopathic infantile hypercalcemia. CONCLUSIONS: The new method showed good utility in clinical settings involving vitamin D deficiency; supplementation with vitamin D and idiopathic infantile hypercalcemia, as well as in animal models with ablation of selected cytochrome P450-containing enzymes involved in vitamin D metabolism.
Combined associations of 25-hydroxivitamin D and parathyroid hormone with diabetes risk and associated comorbidities among U.S. white and black women
(Springer Nature, 2021-09) Xia, Jin; Tu, Wanzhu; Manson, JoAnn E.; Nan, Hongmei; Shadyab, Aladdin H.; Bea, Jennifer W.; Gower, Emily W.; Qi, Lihong; Cheng, Ting-Yuan David; Song, Yiqing; Epidemiology, School of Public Health
Background/objectives: There is evidence of black-white differences in vitamin D status and cardiometabolic health. This study aimed to further evaluate the joint associations of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) with risks of diabetes and related cardiometabolic comorbidities among white and black women. Subjects/methods: We cross-sectionally and prospectively analyzed data from 1850 black and 3000 white postmenopausal women without cardiovascular disease or dialysis at baseline from the Women's Health Initiative-Observational Study. Weighted Cox proportional hazards analyses and weighted logistic regression models were used to examine the joint associations of 25(OH)D and PTH with incident diabetes and prevalence of other diabetes-related cardiometabolic comorbidities (including CKD, hypertension, or obesity). Results: We identified 3322 cases of obesity (n = 1629), hypertension (n = 2759), or CKD (n = 318) at baseline and 453 incident cases of diabetes during 11 years of follow-up. Cross-sectionally, lower 25(OH)D and higher PTH were independently associated with higher prevalence of hypertension [odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.72-0.87 and OR = 1.55; 95% CI: 1.39-1.73] among white women only. When stratified by diabetes status, compared to women with 25(OH)D ≥50 nmol/L and PTH ≤6.89 pmol/L (65 pg/mL), women who did not have diabetes with vitamin D deficiency (<50 nmol/L) and PTH excess (>6.89 pmol/L) had higher prevalence of CKD, hypertension, or obesity (OR = 4.23; 95% CI: 2.90-6.18) than women who had diabetes (OR = 1.89; 95% CI: 0.96-3.71). Prospectively, lower 25(OH)D was associated with lower diabetes incidence [hazard ratio (HR) = 0.73; 95% CI: 0.62-0.86] in white women. Jointly, compared to the group with 25(OH)D ≥50 nmol/L and PTH ≤6.89 pmol/L, white women with 25(OH)D deficiency (<50 nmol/L) had elevated risk for diabetes, regardless of PTH levels. Conclusions: Low 25(OH)D and high PTH were jointly associated with increased risk of diabetes among white women only. Their joint associations with high prevalence of CKD, hypertension, and obesity were more pronounced among women without diabetes.
Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia
(Wiley, 2016-06) Clinkenbeard, Erica L.; Cass, Taryn A.; Ni, Pu; Hum, Julia M.; Bellido, Teresita; Allen, Matthew R.; White, Kenneth E.; Department of Medical and Molecular Genetics, School of Medicine
The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("Δ") had undetectable serum intact FGF23, elevated serum phosphate (p < 0.05), and increased kidney Cyp27b1 mRNA (p < 0.05), similar to global Fgf23-KO mice. To isolate cellular FGF23 responses during phosphate challenge, Fgf23(Δ/f) mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23(Δ/f) /Col2.3-cre(+) and Fgf23(Δ/f) /Dmp1-cre(+) exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre(-) mice had 2.1-fold to 2.5-fold increased serum FGF23 (p < 0.01), but Col2.3-cre(+) mice had no significant increase, and Dmp1-cre(+) mice had only a 37% increase (p < 0.01) despite prevailing hyperphosphatemia in both models. The Fgf23(Δ/f) /Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23(Δ/f) /Col2.3-cre(+) mice had serum FGF23 <4% of Hyp (p < 0.01), and this targeted restriction normalized serum phosphorus and ricketic bone disease. In summary, deleting FGF23 within early osteoblasts and osteocytes demonstrated that both cell types contribute to baseline circulating FGF23 concentrations, and that targeting osteoblasts/osteocytes for FGF23 production can modify systemic responses to changes in serum phosphate concentrations and rescue the Hyp genetic syndrome.
Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period
(Springer, 2019-09-01) Portale, Anthony A.; Carpenter, Thomas O.; Brandi, Maria Luisa; Briot, Karine; Cheong, Hae II; Cohen-Solal, Martine; Crowley, Rachel; Jan De Beur, Suzanne; Eastell, Richard; Imanishi, Yasuo; Imel, Erik A.; Ing, Steven; Ito, Nobuaki; Javaid, Muhammad; Kamenicky, Peter; Keen, Richard; Kubota, Takuo; Lachmann, Robin; Perwad, Farzana; Pitukcheewanont, Pisit; Ralston, Stuart H.; Takeuchi, Yasuhiro; Tanaka, Hiroyuki; Weber, Thomas J.; Yoo, Han-Wook; Zhang, Lin; Theodore-Oklota, Christina; Mealiffe, Matt; San Martin, Javier; Insogna, Karl; Medicine, School of Medicine
Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24–48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.
Disruption of Kidney–Immune System Crosstalk in Sepsis with Acute Kidney Injury: Lessons Learned from Animal Models and Their Application to Human Health
(MDPI, 2022-02-01) LaFavers, Kaice; Medicine, School of Medicine
In addition to being a leading cause of morbidity and mortality worldwide, sepsis is also the most common cause of acute kidney injury (AKI). When sepsis leads to the development of AKI, mortality increases dramatically. Since the cardinal feature of sepsis is a dysregulated host response to infection, a disruption of kidney–immune crosstalk is likely to be contributing to worsening prognosis in sepsis with acute kidney injury. Since immune-mediated injury to the kidney could disrupt its protein manufacturing capacity, an investigation of molecules mediating this crosstalk not only helps us understand the sepsis immune response, but also suggests that their supplementation could have a therapeutic effect. Erythropoietin, vitamin D and uromodulin are known to mediate kidney–immune crosstalk and their disrupted production could impact morbidity and mortality in sepsis with acute kidney injury.
Effects of switching from efavirenz to raltegravir on endothelial function, bone mineral metabolism, inflammation, and renal function: a randomized, controlled trial
(Wolters Kluwer, 2013-11) Gupta, Samir K.; Mi, Deming; Moe, Sharon M.; Dubé, Michael P.; Liu, Ziyue; Medicine, School of Medicine
We performed a randomized controlled trial in 30 HIV-infected participants to either continue tenofovir/emtricitabine/efavirenz (Continuation Group) or switch to tenofovir/emtricitabine/raltegravir (Switch Group) for 24 weeks. There were no significant differences in the changes in flow-mediated dilation, 25(OH) vitamin D, or parathyroid hormone levels. Total cholesterol, high sensitivity C-reactive protein, serum alkaline phosphatase, sCD14 levels, and renal function significantly declined in the Switch Group compared with the Continuation Group; however, sCD163 levels significantly increased in the Switch Group. These findings suggest that raltegravir is not inherently more beneficial to endothelial function compared with efavirenz but may impact renal function and monocyte activation.
FGF23 Synthesis and Activity
(Springer, 2019-03) Noonan, Megan L.; White, Kenneth E.; Medical and Molecular Genetics, School of Medicine
Purpose of review: The phosphaturic hormone FGF23 is produced primarily in osteoblasts/osteocytes and is known to respond to increases in serum phosphate and 1,25(OH)2 vitamin D (1,25D). Novel regulators of FGF23 were recently identified, and may help explain the pathophysiologies of several diseases. This review will focus on recent studies examining the synthesis and actions of FGF23. Recent findings: The synthesis of FGF23 in response to 1,25D is similar to other steroid hormone targets, but the cellular responses to phosphate remain largely unknown. The activity of intracellular processing genes control FGF23 glycosylation and phosphorylation, providing critical functions in determining the serum levels of bioactive FGF23. The actions of FGF23 largely occur through its co-receptor αKlotho (KL) under normal circumstances, but FGF23 has KL-independent activity during situations of high concentrations. Summary: Recent work regarding FGF23 synthesis and bioactivity, as well as considerations for diseases of altered phosphate balance will be reviewed.
Fixation Using Alternative Implants for the Treatment of Hip Fractures
(Wolters Kluwer, 2020-05-21) Sprague, Sheila; Bhandari, Mohit; Bzovsky, Sofia; Scott, Taryn; Thabane, Lehana; Heels-Ansdell, Diane; O’Toole, Robert V.; Howe, Andrea; Gaski, Greg E.; Hill, Lauren C.; Brown, Krista M.; Viskontas, Darius; Zomar, Mauri; Della Rocca, Gregory J.; Slobogean, Gerard P.; Orthopaedic Surgery, School of Medicine
Objectives: To conduct a pilot trial for the Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2) protocol to assess feasibility of a definitive trial. Design: Pilot trial. Setting: Twenty-five clinical sites across North America and Australia were initiated, but enrolment occurred in only 15 North American sites. Patients/participants: Ninety-one randomized adults aged 18 to 60 years with a femoral neck fracture requiring surgical fixation. Intervention: Eligible patients were randomized to receive surgical treatment (sliding hip screw or cancellous screws) AND nutritional supplementation (4000 IU of vitamin D or placebo) for 6 months postfracture. Main outcome measurements: Feasibility outcomes included: clinical site initiation, participant enrolment rate, proportion of participants with complete 12-month follow-up, level of data quality, and rate of protocol adherence (number of randomization errors, crossovers between treatment groups, and daily supplementation adherence). Results: Eighty-six of 91 participants randomized into the pilot trial from 15 North American hospitals were deemed eligible. Four of five primary feasibility criteria were not achieved as we were unable to initiate clinical sites outside of North America and Australia due to feasibility constraints, slow participant enrolment (60 participants recruited over 36 mo), low adherence with daily nutritional supplementation at the 6-week (72.1%), 3-month (60.5%), and 6-month (54.7%) follow-up visits, and a high loss to follow-up rate of 22.1% at 12 months. Conclusions: Despite not meeting key feasibility criteria, we increased our knowledge on the logistics and anticipated barriers when conducting vitamin D supplementation trials in this trauma population, which can be used to inform the design and conduct of future trials on this topic.
Gene-by-Diet Interactions Affect Serum 1,25-Dihydroxyvitamin D Levels in Male BXD Recombinant Inbred Mice
(Oxford University Press, 2016-02) Fleet, James C.; Replogle, Rebecca A.; Reyes-Fernandez, Perla; Wang, Libo; Zhang, Min; Clinkenbeard, Erica L.; White, Kenneth E.; Department of Medical & Molecular Genetics, IU School of Medicine
1,25-Dihydroxyvitamin D (1,25[OH]2D) regulates calcium (Ca), phosphate, and bone metabolism. Serum 1,25(OH)2D levels are reduced by low vitamin D status and high fibroblast growth factor 23 (FGF23) levels and increased by low Ca intake and high PTH levels. Natural genetic variation controls serum 25-hydroxyvitamin D (25[OH]D) levels, but it is unclear how it controls serum 1,25(OH)2D or the response of serum 1,25(OH)2D levels to dietary Ca restriction (RCR). Male mice from 11 inbred lines and from 51 BXD recombinant inbred lines were fed diets with either 0.5% (basal) or 0.25% Ca from 4 to 12 weeks of age (n = 8 per line per diet). Significant variation among the lines was found in basal serum 1,25(OH)2D and in the RCR as well as basal serum 25(OH)D and FGF23 levels. 1,25(OH)2D was not correlated to 25(OH)D but was negatively correlated to FGF23 (r = -0.5). Narrow sense heritability of 1,25(OH)2D was 0.67 on the 0.5% Ca diet, 0.66 on the 0.25% Ca diet, and 0.59 for the RCR, indicating a strong genetic control of serum 1,25(OH)2D. Genetic mapping revealed many loci controlling 1,25(OH)2D (seven loci) and the RCR (three loci) as well as 25(OH)D (four loci) and FGF23 (two loci); a locus on chromosome 18 controlled both 1,25(OH)2D and FGF23. Candidate genes underlying loci include the following: Ets1 (1,25[OH]2D), Elac1 (FGF23 and 1,25[OH]2D), Tbc1d15 (RCR), Plekha8 and Lyplal1 (25[OH]D), and Trim35 (FGF23). This report is the first to reveal that serum 1,25(OH)2D levels are controlled by multiple genetic factors and that some of these genetic loci interact with the dietary environment.

Browsing by Subject "Vitamin D"

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