Abnormal parathyroid hormone stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the hypophosphatemic mouse. Evidence for a generalized defect of vitamin D metabolism.
Abnormal regulation of vitamin D metabolism is a feature of X-linked hypophosphatemic rickets in man and of the murine homologue of the disease in the hypophosphatemic (Hyp)-mouse. We previously reported that mutant mice have abnormally low renal 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity for the prevailing degree of hypophosphatemia. To further characterize this defect, we examined whether Hyp-mouse renal 1 alpha-hydroxylase activity responds normally to other stimulatory and inhibitory controls of enzyme function. We studied stimulation by parathyroid hormone (PTH) using: (a) a calcium-deficient (0.02% Ca) diet to raise endogenous PTH; or (b) 24-h continuous infusion of 0.25 IU/h bovine PTH via osmotic minipump. In both cases enzyme activity of identically treated normal mice increased to greater levels than those attained by Hyp-mice. The relative inability of PTH to stimulate 1 alpha-hydroxylase activity is not a function of the hypophosphatemia in the Hyp-mouse since PTH-infused, phosphate-depleted normal mice sustained a level of enzyme activity greater than that of normal and Hyp-mice. In further studies we investigated inhibition of enzyme activity by using: (a) a calcium-loaded (1.2% Ca) diet to suppress endogenous PTH; or (b) 24-h continuous infusion of 0.2 ng/h 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The 1 alpha-hydroxylase activity of normal and Hyp-mice was significantly reduced to similar absolute levels following maintenance on the calcium-loaded diet. Further, infusion of 1,25(OH)2D3 caused a comparable reduction of 1 alpha-hydroxylase activity in normal, Hyp-, and phosphate-depleted normal mice. These observations indicate that the inhibitory control of 1 alpha-hydroxylase by reduced levels of PTH or increased 1,25(OH)2D3 concentrations is intact in the mutants. However, the inability of PTH and hypophosphatemia to stimulate enzyme activity in a manner analogous to that in normal and phosphate-depleted mice indicates that a generalized defect of 1 alpha-hydroxylase regulation is manifest in Hyp-mice.
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage; D002118:Calcium / Q000172:deficiency; D002136:Calcium, Dietary / Q000008:administration & dosage; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007015:Hypophosphatemia, Familial / Q000201:enzymology*; D007279:Injections, Subcutaneous; D007668:Kidney / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000378:metabolism*; D013997:Time Factors
D002136:Calcium, Dietary; D010281:Parathyroid Hormone; D013250:Steroid Hydroxylases; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium