The discovery of the dual origin of vitamin D either by synthesis in the skin from 7-dehydrocholesterol under the influence of UVB sunlight or from dietary origin quickly enabled the eradication of endemic rickets. It then took about one century to unravel the complex metabolism of vitamin D into a large number of metabolites and a key hormone, 1, 25 (OH) 2D, that acts as a ligand for a nuclear transcription factor, VDR, which like all other nuclear receptors, regulates gene transcription and cell function. The vitamin D endocrine system undoubtedly plays a key role in calcium and bone homeostasis. The widespread presence of VDR and the key activating (1-hydroxylase, CYP27B1) and inactivating (24-hydroxylase, CYP24A1) enzymes in most mammalian cells and the data that 1, 25 (OH) 2D regulates∼ 3% of the mouse and human genome suggest that vitamin D metabolites may also function as a hormone or cytokine for many other cellular functions. The development of mice lacking either VDR or 1-hydroxylase provided the tools for a more careful examination of the global physiologic role of vitamin D. The phenotype of these mice can then also be used to explore whether similar consequences of vitamin D deficiency or excess can be observed in humans.

As for other ligands of nuclear receptors, the spectrum of activities of the vitamin D hormone not only covers a primary target system (calcium and bone homeostasis) but also modifies nearly all cells or tissues including skin and muscle, the cardiovascular and immune systems, glucose homeostasis, and cell proliferation in general. Again, similarly to other nuclear receptor ligands (eg, thyroid hormones), the active vitamin D hormone produced in the kidney plays a hormonal role, whereas the local, extrarenal expression of the 1-hydroxylase enzyme enables a paracrine role for the vitamin D endocrine system. The relative role of the hormonal versus the paracrine function is, however, still largely unsolved. This report compares the essential findings in VDR-null mice with the mostly observational data generated in men to better define the possible complex role of vitamin D for global health.