A kidney-specific control module, located separate to the gene that regulates the vitamin D activation enzyme, was identified by the research team; a collaboration led by the University of Wisconsin-Madison.
Dietary and sun-derived vitamin D is converted to its active hormonal form 1,25 dihydroxyvitamin D3 (calcitriol) in the kidney. Renally produced calcitriol regulates calcium balance. However, calcitriol produced elsewhere in the body plays a different role and appears to be activated via inflammation rather than the enzyme CYP27B1 which regulates its manufacture in the kidneys.
“These results reveal that differential regulation of Cyp27b1 expression represents a mechanism whereby 1,25(OH)2D3 can fulfil separate functional roles: first in the kidney to control mineral homeostasis and second in extrarenal cells to regulate target genes linked to specific biological responses,” explained first author Mark Meyer.
The study finding is significant as it provides the first evidence of a hitherto undiscovered mechanism indicating different regulation of CYP27B1 in kidney and non-kidney cells within the body.
The discovery may eventually enable scientists to develop new treatments for bone, inflammatory and immune disorders involving vitamin D, including multiple sclerosis.
CRISPR Cas-9 Mouse Model
The scientists used the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Cas-9 genetic engineering technique to develop mice with kidney-specific control vitamin D activation.
"Through the creation of these mice, we can turn off endocrine regulation of [calcitriol] production exclusively in the kidney," said Mark Meyer, the research associate who led the new study. "By doing so, we can focus further on the inflammatory regulation.”
In the experiment, the researchers deleted enhancer regions of the CYP27B1 gene, which are located at a distance from the gene which encodes the enzyme.
The researchers found that the induction of CYP27B1 in non-kidney cells using inflammatory lipopolysaccharides was unaffected by the deletion of the enhancer regions of the gene; thus providing evidence of two separate vitamin D activation mechanisms in kidney and non-kidney cells.
Additionally, the researchers suggested that examining genetic mutations in humans, located in the same enhancer regions identified in the mice might yield insights into treatment of skeletal disorders.
Source: Journal of Biological Chemistry
Published online: 14 Aug 2017 DOI: 10.1074/jbc.M117.806901
“A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation”
Authors: Mark B. Meyer, Nancy A. Benkusky, Martin Kaufmann, Seong Min Lee, Melda Onal, Glenville Jones and J. Wesley Pike