Cyp27b1 and Cyp24a1 are reciprocally regulated in the kidney by the key hormones PTH,
FGF23, and 1,25(OH)2D3. Our recent genomic studies in mice identified a complex kidney-specific
enhancer module located within the introns of adjacent Mettl1 (M1) and Mettl21b (M21)
genes that mediate basal and PTH induction of Cyp27b1 as well as suppression by FGF23
and 1,25(OH)2D3. Gross deletion of these segments in mice has severe consequences
on skeletal health, and directly affects Cyp27b1 expression in the kidney. Deletion
of both M1 and M21 submodules together fully eliminates basal Cyp27b1 expression in
the kidney, leading to a systemic and skeletal phenotype similar to that of the Cyp27b1-KO
mouse due to depletion of 1,25(OH)2D3 and high PTH. Cyp24a1 levels in the double KO
mouse were low due to compensatory regulation by elevated PTH and reduced FGF23. However,
expression of Cyp27b1 and retention of its regulation by inflammation (LPS) in the
NRTCs remained unperturbed. Dietary normalization of calcium, phosphate, PTH, and
FGF23 rescues this aberrant phenotype and normalizes the skeletal issues. Cyp24a1
is controlled by its own unique enhancers for 1,25(OH)2D3, FGF23, and PTH. We were
also able to eliminate these activities in mice. Collectively, the hormone-mediated
enhancer regulation of both Cyp27b1 and Cyp24a1 in the kidney is responsible for the
circulating levels of 1,25(OH)2D3 in the blood which in turn primarily affects calcium
and phosphate regulation. Importantly, we can now manipulate this system with our
enhancer deletion animal models to study 1,25(OH)2D3 production in non-renal target
cells and tissues not only in disease, where it is known to affect the immune system,
but also in healthy individuals. Here we will review our studies that have defined
a finely balanced homeostatic control mechanism employed by PTH and FGF23 with catastrophic
toxicity protection from 1,25(OH)2D3 in the genomic regulation of vitamin D metabolism
and its accompanied control of mineral maintenance.