Vitamin D resistance.
Vitamin D is a secosteroid of nutritional origin but can also be generated in the skin by ultraviolet light. After two hydroxylations 1,25-(OH)2 vitamin D avidly binds and activates the vitamin D receptor (VDR), a nuclear transcription factor, hereby regulating a large number of genes. The generation of VDR deficient mice has expanded the knowledge on vitamin D from a calcium-regulating hormone to a humoral factor with extensive actions. The effects of the vitamin D system on calcium and bone homeostasis are largely mediated by promoting active intestinal calcium transport via the induction of the epithelial calcium channel TRPV6. Although VDR is redundant in bone, it may regulate the differentiation and function of several bone cells. In skin, VDR expression in keratinocytes is essential in a ligand-independent manner for the maintenance of the normal hair cycle. Therefore, VDR but not vitamin D deficiency results in alopecia. Moreover, 1,25-(OH)2 vitamin D impairs the proliferation not only of keratinocytes but also of many cell types by regulating the expression of cell cycle genes, leading to a G1 cell cycle arrest. In addition, VDR inactivation in mice results in high renin hypertension, cardiac hypertrophy and thrombogenesis. Finally, a dual effect of vitamin D was observed in the immune system where it stimulates the innate immune system while tapering down excessive activation of the acquired immune system. Taken together, the vitamin D endocrine system not only regulates calcium homeostasis but affects several systems mainly by altering gene expression but also by ligand-independent actions.
Bouillon
Roger
R
Laboratory for Experimental Medicine and Endocrinology, Campus Gasthuisberg, Onderwijs & Navorsing 1, Herestraat 49, bus 902, B-3000 Leuven, Belgium. Roger.Bouillon@med.kuleuven.be
Verstuyf
Annemieke
A
Mathieu
Chantal
C
Van Cromphaut
Sophie
S
Masuyama
Ritsuko
R
Dehaes
Petra
P
Carmeliet
Geert
G
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001842:Bone and Bones / Q000503:physiopathology; D064026:Calbindins; D002117:Calcitriol / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D004351:Drug Resistance; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000502:physiology; D007408:Intestinal Absorption; D051379:Mice; D018908:Muscle Weakness / Q000209:etiology; D009369:Neoplasms / Q000209:etiology; D010641:Phenotype; D018167:Receptors, Calcitriol / Q000502:physiology*; D012279:Rickets / Q000503:physiopathology; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology*
D001647:Bile Acids and Salts; D064026:Calbindins; D018167:Receptors, Calcitriol; D064030:S100 Calcium Binding Protein G; D014807:Vitamin D; D002117:Calcitriol; D002118:Calcium