Vitamin D Binding Protein and Monocyte Response to 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D: Analysis by Mathematical Modeling

Abstract

Vitamin D binding protein (DBP) plays a key role in the bioavailability of active 1,25-dihydroxyvitamin D (1,25(OH)2D) and its precursor 25-hydroxyvitamin D (25OHD), but accurate analysis of DBP-bound and free 25OHD and 1,25(OH)2D is difficult. To address this, two new mathematical models were developed to estimate: 1) serum levels of free 25OHD/1,25(OH)2D based on DBP concentration and genotype; 2) the impact of DBP on the biological activity of 25OHD/1,25(OH)2D in vivo. The initial extracellular steady state (eSS) model predicted that 50 nM 25OHD and 100 pM 1,25(OH)2D), <0.1% 25OHD and <1.5% 1,25(OH)2D are ‘free’ in vivo. However, for any given concentration of total 25OHD, levels of free 25OHD are higher for low affinity versus high affinity forms of DBP. The eSS model was then combined with an intracellular (iSS) model that incorporated conversion of 25OHD to 1,25(OH)2D via the enzyme CYP27B1, as well as binding of 1,25(OH)2D to the vitamin D receptor (VDR). The iSS model was optimized to 25OHD/1,25(OH)2D-mediated in vitro dose-responsive induction of the vitamin D target gene cathelicidin (CAMP) in human monocytes. The iSS model was then used to predict vitamin D activity in vivo (100% serum). The predicted induction of CAMP in vivo was minimal at basal settings but increased with enhanced expression of VDR (5-fold) and CYP27B1 (10-fold). Consistent with the eSS model, the iSS model predicted stronger responses to 25OHD for low affinity forms of DBP. Finally, the iSS model was used to compare the efficiency of endogenously synthesized versus exogenously added 1,25(OH)2D. Data strongly support the endogenous model as the most viable mode for CAMP induction by vitamin D in vivo. These novel mathematical models underline the importance of DBP as a determinant of vitamin D ‘status’ in vivo, with future implications for clinical studies of vitamin D status and supplementation.

Critically Ill Children Have Low Vitamin D Binding Protein, Influencing Bioavailability of Vitamin D

“…Bioavailable 25(OH)D (the free plus albumin bound portions) has been proposed as a better indicator of vitamin D activity (32)(33)(34), possibly explaining discrepancies between findings of vitamin D effect on health outcomes in studies relying on total 25(OH)D. Several studies have identified a strong relationship between bioavailable vitamin D and indicators of vitamin D status such as bone mineral density and parathyroid hormone (32,33). Bioavailable 25(OH)D can be calculated using several equations and a mathematical model, which incorporate 25(OH)D, VDBP, albumin levels, and VDBP binding affinity by haplotype to varying degrees (32)(33)(34). Recently, an assay of free 25(OH)D has become commercially available, and a comparison of the calculated to measured free 25(OH)D showed that a calculation that does not incorporate VDBP binding affinity overestimates the measured levels (35).…”

“…In addition, certain disease states, including diffuse inflammation and critical illness, have been shown to be associated with lower VDBP levels (44,46). VDBP concentration and haplotype influence the proportion of bioavailable vitamin D (32)(33)(34)47), meaning that the biologic activity of vitamin D could be similar in patients with widely different total 25(OH)D levels. We sought to determine VDBP levels and to identify patient-related factors, including genotype, that may influence these levels in critically ill children.…”

“…Genotype information was available in 205 subjects and was used to calculate bioavailable 25(OH)D using the published algorithm as described in the METHODS (34). The median calculated bioavailable 25(OH)D level was 4.33 ng/ml (range, 0.54-18.54 ng/ml).…”

MANAGEMENT OF ENDOCRINE DISEASE: Value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation

“…This has obvious important clinical implications, particularly in redefining worldwide vitamin D status (38), as demonstrated in a recent paper by Perna et al Recently, the interest in DBP has considerably increased. DBP circulates in three major polymorphic forms, thus producing six allelic combinations occurring at different frequencies among ethnic populations (44). The different allele forms of DBP circulate at varying concentrations and possess different binding affinities for 25(OH)D and 1,25(OH) 2 D; therefore, both these variables have the potential to influence bioavailability of vitamin D (44).…”

“…DBP circulates in three major polymorphic forms, thus producing six allelic combinations occurring at different frequencies among ethnic populations (44). The different allele forms of DBP circulate at varying concentrations and possess different binding affinities for 25(OH)D and 1,25(OH) 2 D; therefore, both these variables have the potential to influence bioavailability of vitamin D (44). These data are in accordance with the recent genome-wide association studies showing that lower affinity forms of DBP are associated with lower circulating levels of 25(OH)D so that the affinity of the binding may regulate both the total and free 25(OH)D levels (33,45) (Fig.…”