Genomic Mechanisms Governing Mineral Homeostasis and the Regulation and Maintenance of Vitamin D Metabolism

Our recent genomic studies identified a complex kidney-specific enhancer module located within the introns of adjacent (M1) and (M21) genes that mediate basal and PTH induction of , as well as suppression by FGF23 and 1,25-dihydroxyvitamin D [1,25(OH)D]. The tissue specificity for this regulatory module appears to be localized exclusively to renal proximal tubules. Gross deletion of these segments in mice has severe consequences on skeletal health, and directly affects expression in the kidney. Deletion of both the M1 and M21 submodules together almost completely eliminates basal expression in the kidney, creating a renal specific pseudo-null mouse, resulting in a systemic and skeletal phenotype similar to that of the -KO mouse caused by high levels of both 25-hydroxyvitamin D [25(OH)D] and PTH and depletion of 1,25(OH)D. levels in the double KO mouse also decrease because of compensatory downregulation of the gene by elevated PTH and reduced FGF23 that is mediated by an intergenic module located downstream of the gene. Outside of the kidney in nonrenal target cells (NRTCs), expression of in these mutant mice was unaffected. Dietary normalization of calcium, phosphate, PTH, and FGF23 rescues the aberrant phenotype of this mouse and normalizes the skeleton. In addition, both the high levels of 25(OH)D were reduced and the low levels of 1,25(OH)D were fully eliminated in these mutant mice as a result of the rescue-induced normalization of renal . Thus, these hormone-regulated enhancers for both and in the kidney are responsible for the circulating levels of 1,25(OH)D in the blood. The retention of and expression in NRTCs of these endocrine 1,25(OH)D-deficient mice suggests that this pseudo-null mouse will provide a model for the future exploration of the role of NRTC-produced 1,25(OH)D in the hormone's diverse noncalcemic actions in both health and disease. © 2020 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.