Abnormal Regulation of Renal 25‐Hydroxyvitamin D‐1α‐Hydroxylase Activity in X‐Linked Hypophosphatemia: A Translational or Post‐Translational Defect

• Published in: Journal of bone and mineral research Vol. 18; no. 3; pp. 434 - 442
• Main Authors: Fujiwara, Ikuma, Aravindan, Rolands, Horst, Ron L, Drezner, Marc K
• Format: Journal Article
• Language: English
• Published: Washington, DC John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR) 01.03.2003; American Society for Bone and Mineral Research
• Subjects: Biological and medical sciences; CYP27B1; Diseases of the osteoarticular system; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; parathyroid hormone; phosphate; rickets; thyrocalcitonin; Diseases of the osteoarticular system; Tubulopathy; Bone disease; Hypophosphatemic rickets; Kidney; Posttranslational modification; CYP27B1; Enzymatic activity; Vitamin D; Calcitonin; Translating; Anomaly; thyrocalcitonin; Kidney disease; Urinary system disease; Pathophysiology; Enzyme; Steroid hormone; Hydroxylase; Rodentia; phosphate; Metabolism; Genetic disease; Vertebrata; Mammalia; Urinary system; Mouse; Vitamin resistant rickets; Parathyroid hormone; Animal; Cholecalciferol(25-hydroxy); Hormonal regulation; Thyroid hormone; Oxidoreductases; rickets
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.2003.18.3.434

The hyp mouse exhibits abnormal metabolic/hormonal regulation of renal 25(OH)D‐1α‐hydroxylase activity. Whether this results from aberrant transcriptional regulation of the 1α‐hydroxylase gene, CYP27B1, remains unknown. To investigate this possibility, we compared phosphate and parathyroid hormone effects on renal proximal convoluted tubule and thyrocalcitonin effects on proximal straight tubule enzyme activity and mRNA expression in normal and hyp mice. We assayed 25(OH)D‐1α‐hydroxylase activity by measuring 1,25(OH)2D production and mRNA by ribonuclease protection. Phosphate‐depleted mice exhibited a 3‐fold increment of 25(OH)D‐1α‐hydroxylase activity compared with normals, whereas hyp mice displayed no enhanced enzyme function. Phosphate‐depleted mice concurrently displayed a 2‐fold increase in mRNA transcripts; in contrast, despite failure to alter enzyme activity, hyp mice exhibited a similar increment in mRNA transcripts. Parathyroid hormone stimulation of normal mice increased 25(OH)D‐1α‐hydroxylase activity 10‐fold, while eliciting only a 2‐fold increment in hyp mouse enzyme function. This disparity occurred despite increments of mRNA transcripts to comparable levels (22.2 ± 3.5‐ vs. 19.9 ± 1.8‐fold). The dissociation between phosphate‐ and parathyroid hormone‐mediated transcriptional activity and protein function was not universal. Thus, thyrocalcitonin stimulation of normal and hyp mice resulted in comparable enhancement of mRNA transcripts and enzyme activity. These observations indicate that abnormal regulation of vitamin D metabolism in hyp mice occurs in the proximal convoluted tubule and results, not from aberrant transcriptional regulation, but from a defect in translational or post‐translational activity.