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1?,25(OH)(2)-Vitamin D3 increases dysferlin expression in vitro and in a human clinical trial.

ABSTRACT: Dysferlinopathies are a heterogenous group of autosomal recessive inherited muscular dystrophies caused by mutations in DYSF gene. Dysferlin is expressed mainly in skeletal muscle and in monocytes and patients display a severe reduction or absence of protein in both tissues. Vitamin D3 promotes differentiation of the promyelocytic leukemia HL60 cells. We analyzed the effect of vitamin D3 on dysferlin expression in vitro using HL60 cells, monocytes and myotubes from controls and carriers of a single mutation in DYSF. We also performed an observational study with oral vitamin D3 in a cohort of 21 carriers. Fifteen subjects were treated for 1 year and dysferlin expression in monocytes was analysed before and after treatment. Treatment with vitamin D3 increased expression of dysferlin in vitro. The effect of vitamin D3 was mediated by both a nongenomic pathway through MEK/ERK and a genomic pathway involving binding of vitamin D3 receptor to the dysferlin promoter. Carriers treated with vitamin D3 had significantly increased expression of dysferlin in monocytes compared with nontreated carriers (P < 0.05). These findings will have important therapeutic implications since a combination of different molecular strategies together with vitamin D3 uptake could increase dysferlin expression to nonpathological protein levels.

SUBMITTER: De Luna N

PROVIDER: S-EPMC3464637 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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1α,25(OH)(2)-Vitamin D3 increases dysferlin expression in vitro and in a human clinical trial.

De Luna Noemi N Díaz-Manera Jordi J Paradas Carmen C Iturriaga Cristina C Rojas-García Ricardo R Araque Josefa J Genebriera Mireia M Gich Ignasi I Illa Isabel I Gallardo Eduard E

Molecular therapy : the journal of the American Society of Gene Therapy 20120821 10

Dysferlinopathies are a heterogenous group of autosomal recessive inherited muscular dystrophies caused by mutations in DYSF gene. Dysferlin is expressed mainly in skeletal muscle and in monocytes and patients display a severe reduction or absence of protein in both tissues. Vitamin D3 promotes differentiation of the promyelocytic leukemia HL60 cells. We analyzed the effect of vitamin D3 on dysferlin expression in vitro using HL60 cells, monocytes and myotubes from controls and carriers of a sin ...[more]

PMID: 22910291

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Project description:RationalePatients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS).MethodsBalb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined.ResultsMice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A.ConclusionsVD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.

Project description:BackgroundVitamin-D2 (D2) treatment has been associated with a decrease in 25-hydroxy (25(OH)) vitamin-D3 (D3) level, suggesting that D3 treatment would be preferred to raise total 25(OH) vitamin-D (D) level. We postulated that D2 treatment-associated decrease in 25(OH)D3 level is related to the increase in 25(OH)D level rather than being D2-specific, and thus there would be a similar D3 treatment-associated decrease in 25(OH)D2 level.MethodsFifty volunteers were block-randomized to 50,000 IU D2 or placebo orally once (study-1) and fifty volunteers received 50,000 IU D2 orally once and 4 days later block-randomized to 50,000 IU D3 or placebo orally once (study-2). Interventions were concealed from volunteers and research coordinators and blindly-administered. Serum 25(OH)D2 and 25(OH)D3 levels were blindly-determined at baseline and days 14, 28, 42, and 56, post-randomization by high performance liquid chromatography assay. Results of 97 participants were analyzed. Primary outcome measure was day-28 D2-associated change in 25(OH)D3 level in study-1 and D3-associated change in 25(OH)D2 level in study-2, adjusted for baseline levels.ResultsMean (95% confidence interval) difference between the active and placebo arms in the decrease in day-28 25(OH)D3 (study-1) and 25(OH)D2 (study-2) levels was 13.2 (9.7 to 16.6) and 9.8 (5.2 to 14.4) nmol/L, respectively. Corresponding differences at day-56 were 10.8 (6.8 to 14.8) and 1.7 (- 7.6 to 11.1) nmol/L, respectively. The difference between the placebo and active arms in area-under-the-curve at day-28 (AUC28) and day-56 (AUC56) were 262.3 (197.8 to 326.7) and 605.1 (446.3 to 784.0) for 25(OH)D3 (study-1) and 282.2 (111.2 to 453.3) and 431.2 (179.3 to 683.2) nmol.d/L for 25(OH)D2 (study-2), respectively. There were significant correlations between day-28 changes in 25(OH)D2 and 25(OH)D3 levels in study-1 (rho = - 0.79, p < 0.001) and study-2 (rho = - 0.36, p = 0.01), and between day-28 changes in 25(OH)D2 level and baseline 25(OH)D level in study-2 (rho = - 0.42, p = 0.003).ConclusionsCompared to placebo, D3 treatment is associated with a decrease in 25(OH)D2 level similar in magnitude to D2-treatment associated decrease in 25(OH)D3 level; however, the D3-placebo difference in 25(OH)D2 level is shorter-lasting. Changes in 25(OH)D2 and 25(OH)D3 levels are correlated with each other and with baseline 25 (OH) D levels, suggesting a common regulatory mechanism.Trial registrationClinicalTrial.gov identifier: NCT03035084 (registered January 27, 2017).

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1?,25(OH)(2)-Vitamin D3 increases dysferlin expression in vitro and in a human clinical trial.

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1α,25(OH)(2)-Vitamin D3 increases dysferlin expression in vitro and in a human clinical trial.

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