Vitamin D: calcium and bone homeostasis during evolution.

Vitamin D3 is already found early in the evolution of life but essentially as inactive end products of the photochemical reaction of 7-dehydrocholestol with ultraviolet light B. A full vitamin D (refers to vitamin D2 and D3) endocrine system, characterized by a specific VDR (vitamin D receptor, member of the nuclear receptor family), specific vitamin D metabolizing CYP450 enzymes regulated by calciotropic hormones and a dedicated plasma transport-protein is only found in vertebrates. In the earliest vertebrates (lamprey), vitamin D metabolism and VDR may well have originated from a duplication of a common PRX/VDR ancestor gene as part of a xenobiotic detoxification pathway. The vitamin D endocrine system, however, subsequently became an important regulator of calcium supply for an extensive calcified skeleton. Vitamin D is essential for normal calcium and bone homeostasis as shown by rickets in vitamin D-deficient growing amphibians, reptiles, birds and mammals. From amphibians onward, bone is gradually more dynamic with regulated bone resorption, mainly by combined action of PTH and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the generation and function of multinucleated osteoclasts. Therefore, bone functions as a large internal calcium reservoir, under the control of osteoclasts. Osteocytes also display a remarkable spectrum of activities, including mechanical sensing and regulating mineral homeostasis, but also have an important role in global nutritional and energy homeostasis. Mineralization from reptiles onward is under the control of well-regulated SIBLING proteins and associated enzymes, nearly all under the control of 1,25(OH)2D3. The vitamin D story thus started as inert molecule but gained an essential role for calcium and bone homeostasis in terrestrial animals to cope with the challenge of higher gravity and calcium-poor environment.