Redefining Human Vitamin D Sufficiency: Back to the Basics

Abstract

The role of the endocrine vitamin D pathway in regulating the serum calcium concentration in man is well described. In the presence of a low serum calcium level, the vitamin D metabolic pathway is called upon to produce more of the active vitamin D hormone, 1, 25-dihydroxyvitamin D (1, 25-D), via up-regulation of the CYP27b1-hydroxylase activity in the kidney. The consequence is mobilization of skeletal calcium stores to return the circulating calcium level back to the normal range. On the other hand, when the serum calcium level increases, endocrine forces move to suppress renal 1, 25D production and squelch bone resorption. It is now known that vitamin D metabolites also operate in an autocrine, paracrine and intracrine mode to control vitamin D receptor-directed biological responses at the tissue level. Because the metabolism and action of vitamin D occurs at the tissue level in this situation, use of circulating vitamin D metabolites and biomarkers to ascertain the local action of the vitamin D pathway is often misleading. This mini-review seeks to compare and contrast the operation of the vitamin D pathway at the endocrine and tissue level.

Figure 1

The endocrinology of vitamin D. The left panel depicts the essentials of the endocrine synthesis, metabolism and action of vitamin D. The key enzyme in the synthesis of the active, vitamin D receptor-(VDR) interacting metabolite, 1,25-dihydroxyvitamin D, is the CYP27b1-hydroxylase. In normal human endocrine physiology the CYP27b1-hydroxylase is expressed principally in the kidney but also in the placenta. The catabolic CYP24a1-24-hydroxylase is ubiquitously distributed among human tissues and serves to inactivate 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. The right panel shows the endocrine responses of the vitamin D pathway to a hypocalcemic challenge and the human host's use of the skeleton to restore blood calcium levels back to normal. Abbreviations include: CaSR, calcium sensing receptor; PTH, parathyroid hormone; PTH/PTHrP, receptor for PTH and parathyroid hormone-related protein; DBP, serum vitamin D binding protein; RXR, retinoid X receptor; VDRE, vitamin D response element; Ca²⁺, calcium ion; PO₄³⁻, phosphate ion; RANKL, receptor activator of nuclear factor kappa-B ligand; FGF23, fibroblast growth factor-23. Figure adapted with the permission of the original authors.

Figure 2

The intra-, auto- and paracrinology of the vitamin D system in the local inflammatory microenvironment. The left panel shows the intracellular metabolism of extracellular substrate 25-dihydroxyvitamin D (25D) and intracrine action of the CYP27b1-hydroxylase product 1,25-dihydroxyvitamin D metabolite (1,25D) in the Toll-like receptor-(TLR2-1 dimer) activated human macrophage. TLR2-1 stimulation initiates expression of the vitamin D receptor (VDR) and CYP27b1-hydroxylase genes. Intracellularly-synthesized 1,25Ddrives expression of the anti-microbial gene cathelicidin (LL37) to kill ingested Mycobacterium tuberculosis (M. tb). The right panel shows the signaling pathways in the intracrine, autocrine and paracrine modes that mediate the concerted TLR-driven, interferon-gamma-(IFN-γ) amplified innate immune response in the macrophage and the IFN-β- and 1,25D-directed feedback inhibited adaptive immune response of activated, VDR-expressing Th lymphocytes (Th). Other abbreviations include: DBP, serum vitamin D binding protein; and myD88, myeloid differentiation primary response gene (88). Figure adapted with the permission of the original authors.