100 YEARS OF VITAMIN D: Historical aspects of vitamin D

Abstract

Vitamin D has many physiological functions including upregulation of intestinal calcium and phosphate absorption, mobilization of bone resorption, renal reabsorption of calcium as well as actions on a variety of pleiotropic functions. It is believed that many of the hormonal effects of vitamin D involve a 1,25-dihydroxyvitamin D3-vitamin D receptor-mediated transcriptional mechanism involving binding to the cellular chromatin and regulating hundreds of genes in many tissues. This comprehensive historical review provides a unique perspective of the many steps of the discovery of vitamin D and its deficiency disease, rickets, stretching from 1650 until the present. The overview is divided into four distinct historical phases which cover the major developments in the field and in the process highlighting the: (a) first recognition of rickets or vitamin D deficiency; (b) discovery of the nutritional factor, vitamin D and its chemical structure; (c) elucidation of vitamin D metabolites including the hormonal form, 1,25-dihydroxyvitamin D3; (d) delineation of the vitamin D cellular machinery, functions and vitamin D-related diseases which focused on understanding the mechanism of action of vitamin D in its many target cells.

Keywords: 7-dehydrocholesterol; UV light; calcium and phosphate homeostasis; rickets and osteomalacia; vitamin D; vitamin D analogs; vitamin D function; vitamin D metabolism.

Figure 1

Lithograph from Glisson’s De Rachitide (1671) (10) also depicted as the frontispiece of Hess AF’s book (11) Rickets Including Osteomalacia and Tetany. Reproduced from the US National Library digital collection. Credit: Rickets, including osteomalacia and tetany / by Alfred F Hess.

Figure 2

Structures of vitamin D₂ and D₃. The two versions of vitamin D differ only in their side chains vitamin D₂ possessing an additional C-22-23 double bond and a C-24 methyl group. The modifications make little significant difference in their metabolism or biological actions.

Figure 3

Metabolism and mechanism of action of vitamin D₃. Skin-synthesized or dietary vitamin D₃ is converted via a two-step hydroxylation process into the active hormonal form 1,25-(OH)₂D₃. The hormone binds to the vitamin D receptor (VDR) and regulates serum calcium (sCa²⁺) and serum phosphate (sPO₄) levels ensuring sufficient minerals for normal cellular activity around the body including bone. Insufficient vitamin D results in insufficient 1,25-(OH)₂D₃ and vitamin deficiency rickets. Circled in red are the proteins in the vitamin D-specific machinery that when mutated also result in some type of rickets. Circled in blue is the enzyme CYP24A1 that when mutated results in elevated 1,25-(OH)₂D₃ and hypercalcemia and/or kidney stones.