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ARS Home » Midwest Area » Ames, Iowa » National Animal Disease Center » Ruminant Diseases and Immunology Research » Research » Publications at this Location » Publication #177378
Title: EVIDENCE OF ABNORMAL TRANSLATIONAL REGULATION OF RENAL 25-HYDROXYVITAMIN D-1ALPHA-HYDROXYLASE ACTIVITY IN THE HYP-MOUSE

Author
item YUAN, BAOZHI - UNIV. WI, MADISON
item XING, YINA - UNIV. WI, MADISON
item Horst, Ronald
item DREZNER, MARC - UNIV. WI, MADISON

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/1/2004
Publication Date: 8/20/2004
Citation: Yuan, B., Xing, Y., Horst, R.L., Drezner, M.K. 2004. Evidence of abnormal translational regulation of renal 25-hydroxyvitamin d-1alpha-hydroxylase activity in the hyp-mouse. Endocrinology. 145(8):3804-3812.

Interpretive Summary: X-Linked hypophosphatemia is a genetic disease in humans which results in abnormal bone development. This disorder is not common, with estimated occurrence between 1/100,000 to 1/1,000,000 live births. This disorder was once called 'vitamin D-resistance rickets,' a reference to the poor therapeutic response to doses of vitamin D used to treat vitamin D deficiency. There is an experimental animal which has been used quite extensively to study this abnormality. The model has been tabbed the hyp-mouse model, which exhibits similar abnormalities to the human condition. The present experiments demonstrate that kidneys from hyp-mice exhibit abnormal conversion of vitamin D to its active form, 1,25-dihydroxyvitamin D. The results will be of particular interest and importance to clinicians and medical researchers studying this disease.

Technical Abstract: Hyp-mice exhibit abnormal regulation of 25-hydroxyvitamin D-1alpha-hydroxylase activity. Previous observations suggest such aberrant modulation is post-transcriptional. To investigate this possibility further we examined if hyp-mice manifest abnormal translation of 25(OH)D-1alpha-hydroxylase mRNA. We compared phosphate, parathyroid and thyrocalcitonin effects on renal 25-hydroxyvitamin D-1alpha-hydroxylase protein, as well as mRNA and enzyme activity in normal and hyp-mice. We assayed protein by Western blots, mRNA by real-time RT-PCR and enzyme activity by measuring 1,25-dihydroxyvitamin D production. While phosphate depleted mice exhibited enhanced enzyme function, with significantly increased mRNA and protein expression, hyp-mice comparably increased mRNA, but failed to augment enzyme activity, concordant with an inability to increase protein expression. Parathyroid hormone stimulation increased mRNA and protein expression, as well as enzyme activity in normal mice, but in hyp-mice, despite effecting mRNA enhancement, did not increment enzyme function or protein. The inability of hypophosphatemia and parathyroid hormone to increase 25-hydroxyvitamin D-1alpha-hydroxylase activity and protein expression in hyp-mice was not universal since thyrocalcitonin stimulation was normal, suggesting proximal convoluted tubule localization of the defect. These data, in accord with absent undue enhancement of protein expression in hyp-mice treated with protease inhibitors, establish that aberrant regulation of vitamin D metabolism results from abnormal translational activity.