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Magnesium Treatment on Vitamin D Metabolism in Participants Completed Personalized Prevention of Colorectal Cancer Trial

ABSTRACT: One striking observation is that a large portion of the inter-person variation in serum 25-hydroxyvitamin D (25(OH)D) levels is unexplained. In vitro and in vivo studies indicate vitamin D synthesizing and metabolizing enzymes are Mg-dependent. Magnesium (Mg) supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. The investigators reported in 2013 from observational studies conducted in the general US population that Mg intake significantly interacted with vitamin D intake in affecting vitamin D status as well as interacted with serum 25(OH)D in risk of cardiovascular disease mortality and, maybe, colorectal cancer mortality. The potential interaction between Mg and vitamin D was supported by two subsequent studies, including a Finnish cohort study and a mouse study. In the parent study (Personalized Prevention of Colorectal Cancer Trial, NCT01105169), the investigators proposed to measure blood concentration of total 25(OH)D as a secondary aim using Elisa approach. However, following the novel finding of Mg-vitamin D interaction published by the investigators in 2013, they submitted a separate grant application to NCI which was funded in 2014. In the new study, the investigators proposed to use a LC-MS approach, which is more accurate and specific than an Elisa method, to measure 5 vitamin D metabolites. This new ancillary study allows the investigators to evaluate whether Mg supplementation differentially affects vitamin D synthesis and metabolism dependent on baseline serum 25(OH)D levels using existing biospecimens collected in our double-blind placebo-controlled randomized chemoprevention trial.

DISEASE(S): Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2253003 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Fibroblast growth factor 23 (FGF23) is produced and secreted by osteocytes and is essential for maintaining phosphate homeostasis. One of the main regulators of FGF23, 1,25-dihydroxyvitamin D (1,25(OH)2D3), is primarily synthesized in the kidney from 25-hydroxyvitamin D (25(OH)D) by 1α-hydroxylase (encoded by CYP27B1). Hitherto, it is unclear whether osteocytes can convert 25(OH)D and thereby allow for 1,25(OH)2D3 to induce FGF23 production and secretion locally. Here, we differentiated MC3T3-E1 cells towards osteocyte-like cells expressing and secreting FGF23. Treatment with 10-6 M 25(OH)D resulted in conversion of 25(OH)D to 150 pmol/L 1,25(OH)2D3 and increased FGF23 expression and secretion but the converted amount of 1,25(OH)2D3 was insufficient to trigger an FGF23 response, so the effect on FGF23 was most likely directly caused by 25(OH)D. Interestingly, combining phosphate with 25(OH)D resulted in a synergistic increase in FGF23 expression and secretion, likely due to activation of additional signaling pathways by phosphate. Blockage of the vitamin D receptor (VDR) only partially abolished the effects of 25(OH)D or 25(OH)D combined with phosphate on Fgf23, while completely inhibiting the upregulation of cytochrome P450 family 24 subfamily A member 1 (Cyp24a1), encoding for 24-hydroxylase. RNA sequencing and in silico analyses showed that this could potentially be mediated by the nuclear receptors Retinoic Acid Receptor b (RARB) and Estrogen Receptor 2 (ESR2). Taken together, we demonstrate that osteocytes are able to convert 25(OH)D to 1,25(OH)2D3, but this is insufficient for FGF23 activation, implicating a direct effect of 25(OH)D in the regulation of FGF23, which occurs at least partially independent from its cognate vitamin D receptor Moreover, phosphate and 25(OH)D synergistically increase expression and secretion of FGF23, which warrants investigating consequences in patients receiving a combination of vitamin D analogues and phosphate supplements. These observations help us to further understand the complex relations between, phosphate, vitamin D and FGF23.

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Magnesium Treatment on Vitamin D Metabolism in Participants Completed Personalized Prevention of Colorectal Cancer Trial

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