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Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol.

ABSTRACT: The optimal circulating concentration of 25(OH) vitamin D is controversial.The aim was to investigate if FGF-23 and 24,25(OH)2D can guide cholecalciferol replacement.Oral cholecalciferol (10,000 IU weekly) administered to subjects with 25(OH)D levels < 20 ?g/mL and eGFR > 60 mL/min/1.73 m(2) (n = 25), chronic kidney disease (CKD) (n = 27), or end stage renal disease (ESRD) (n = 14).The study was conducted at the Veterans Affairs clinics.Serum FGF-23, PTH, 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, calcium, and phosphorous concentrations, and urinary excretion of calcium and phosphorus at baseline and after 8 weeks of treatment.Cholecalciferol treatment increased concentrations of serum 25(OH)D by (19.3 ± 8 ?g/mL, P = .001; 12.2 ± 9 ?g/mL, P = .0001) and 24,25(OH)2D (1.14 ± 0.89 ?g/mL, P = .0024; 1.0 ± 0.72 ?g/mL P = .0002), and reduced serum PTH (-11 ± 21 pg/mL, P = .0292; -42 ± 68 pg/mL, P = .0494) in normal and CKD subjects, respectively. Cholecalciferol increased serum FGF-23 levels only in normal subjects (44 ± 57 ?g/mL, P = .01). Increments in serum 25(OH)D positively correlated with serum FGF-23 and 24,25(OH)2D and negatively correlated with PTH. In ESRD, cholecalciferol administration increased 25(OH)D by (16.6 ± 6.6 ?g/mL P ? .05) without changing 24,25(OH)2D, FGF-23 or PTH levels.Modest elevations of serum 25(OH)D levels after cholecalciferol treatment are sufficient to induce compensatory degradative pathways in patients with sufficient renal reserves, suggesting that optimal circulating 25(OH)D levels are approximately 20 ?g/mL. In addition, catabolism of 25(OH)D may also contribute to the low circulating vitamin D levels in CKD, since elevations of FGF-23 in CKD are associated with increased 24,25(OH)2D after cholecalciferol administration.

SUBMITTER: Alshayeb H

PROVIDER: S-EPMC4184071 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol.

Alshayeb Hala H Showkat Arif A Wall Barry M BM Gyamlani Geeta G GG David Valentin V Quarles L Darryl LD

The Journal of clinical endocrinology and metabolism 20140624 10

<h4>Context</h4>The optimal circulating concentration of 25(OH) vitamin D is controversial.<h4>Objective</h4>The aim was to investigate if FGF-23 and 24,25(OH)2D can guide cholecalciferol replacement.<h4>Design</h4>Oral cholecalciferol (10,000 IU weekly) administered to subjects with 25(OH)D levels < 20 ηg/mL and eGFR > 60 mL/min/1.73 m(2) (n = 25), chronic kidney disease (CKD) (n = 27), or end stage renal disease (ESRD) (n = 14).<h4>Setting</h4>The study was conducted at the Veterans Affairs cl ...[more]

PMID: 24960544

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Project description:Although cognitive impairment is common in hemodialysis patients, the etiology of and risk factors for its development remain unclear. Fibroblast growth factor 23 (FGF-23) levels are elevated in hemodialysis patients and are associated with increased mortality and left ventricular hypertrophy. Despite FGF-23 being found within the brain, there are no prior studies assessing whether FGF-23 levels are associated with cognitive performance. We measured FGF-23 in 263 prevalent hemodialysis patients in whom comprehensive neurocognitive testing was also performed. The cross-sectional association between patient characteristics and FGF-23 levels was assessed. Principal factor analysis was used to derive two factors from cognitive test scores, representing memory and executive function, which carried a mean of 0 and a standard deviation of 1. Multivariable linear regression adjusting for age, sex, education status, and other relevant covariates was used to explore the relationship between FGF-23 and each factor. Mean age was 63 years, 46% were women and 22% were African American. The median FGF-23 level was 3098 RU/mL. Younger age, lower prevalence of diabetes, longer dialysis vintage, and higher calcium and phosphorus were independently associated with higher FGF-23 levels. Higher FGF-23 was independently associated with a lower memory score (per doubling of FGF-23, β = -0.08 SD [95% confidence interval, CI: -0.16, -0.01]) and highest quartile vs. lowest quartile (β = -0.42 SD [-0.82, -0.02]). There was no definite association of FGF 23 with executive function when examined as a continuous variable (β = -0.03 SD [-0.10, 0.04]); however, there was a trend in the quartile analysis (β = -0.28 SD [-0.63, 0.07], P = 0.13, for 4th quartile vs. 1st quartile). FGF-23 was associated with worse performance on a composite memory score, including after adjustment for measures of mineral metabolism. High FGF-23 levels in hemodialysis patients may contribute to cognitive impairment.

Project description:Previously, we demonstrated i) that ergocalciferol (vitamin D2) increases axon diameter and potentiates nerve regeneration in a rat model of transected peripheral nerve and ii) that cholecalciferol (vitamin D3) improves breathing and hyper-reflexia in a rat model of paraplegia. However, before bringing this molecule to the clinic, it was of prime importance i) to assess which form - ergocalciferol versus cholecalciferol - and which dose were the most efficient and ii) to identify the molecular pathways activated by this pleiotropic molecule. The rat left peroneal nerve was cut out on a length of 10 mm and autografted in an inverted position. Animals were treated with either cholecalciferol or ergocalciferol, at the dose of 100 or 500 IU/kg/day, or excipient (Vehicle), and compared to unlesioned rats (Control). Functional recovery of hindlimb was measured weekly, during 12 weeks, using the peroneal functional index. Ventilatory, motor and sensitive responses of the regenerated axons were recorded and histological analysis was performed. In parallel, to identify the genes regulated by vitamin D in dorsal root ganglia and/or Schwann cells, we performed an in vitro transcriptome study. We observed that cholecalciferol is more efficient than ergocalciferol and, when delivered at a high dose (500 IU/kg/day), cholecalciferol induces a significant locomotor and electrophysiological recovery. We also demonstrated that cholecalciferol increases i) the number of preserved or newly formed axons in the proximal end, ii) the mean axon diameter in the distal end, and iii) neurite myelination in both distal and proximal ends. Finally, we found a modified expression of several genes involved in axogenesis and myelination, after 24 hours of vitamin supplementation. Our study is the first to demonstrate that vitamin D acts on myelination via the activation of several myelin-associated genes. It paves the way for future randomised controlled clinical trials for peripheral nerve or spinal cord repair.

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Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol.

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Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol.

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