Genomically anchored vitamin D receptor mediates an abundance of bioprotective actions elicited by its 1,25-dihydroxyvitamin D hormonal ligand

The nuclear vitamin D receptor (VDR) mediates the actions of its physiologic 1,25-dihydroxyvitamin D₃ (1,25D) ligand produced in kidney and at extrarenal sites during times of physiologic and cellular stress. The ligand-receptor complex transcriptionally controls genes encoding factors that regulate calcium and phosphate sensing/transport, bone remodeling, immune function, and nervous system maintenance. With the aid of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), 1,25D/VDR primarily participates in an intricate network of feedback controls that govern extracellular calcium and phosphate concentrations, mainly influencing bone formation and mineralization, ectopic calcification, and indirectly supporting many fundamental roles of calcium. Beyond endocrine and intracrine effects, 1,25D/VDR signaling impacts multiple biochemical phenomena that potentially affect human health and disease, including autophagy, carcinogenesis, cell growth/differentiation, detoxification, metabolic homeostasis, and oxidative stress mitigation. Several health advantages conferred by 1,25D/VDR appear to be promulgated by induction of klotho, an anti-aging renal peptide hormone which functions as a co-receptor for FGF23 and, like 1,25D, regulates nrf2, foxo, mTOR and other cellular protective pathways. Among hundreds of genes for which expression is modulated by 1,25D/VDR either primarily or secondarily in a cell-specific manner, the resulting gene products (in addition to those expressed in the classic skeletal mineral regulatory tissues kidney, intestine, and bone), fall into multiple biochemical categories including apoptosis, cholesterol homeostasis, glycolysis, hypoxia, inflammation, p53 signaling, unfolded protein response and xenobiotic metabolism. Thus, 1,25D/VDR is a bone mineral control instrument that also signals the maintenance of multiple cellular processes in the face of environmental and genetic challenges.