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.

Abstract

Abnormal regulation of vitamin D metabolism is a feature of Xlinked 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-la-hydroxylase (la-hydroxylase) activity for the prevailing degree of hypophosphatemia. To further characterize this defect, we examined whether Hyp-mouse renal la-hydroxylase activity responds normally to other stimulatory and inhibitory controls of enzyme function. We studied stimulation by parathyroid hormone (PTH) using: (a) a calciumdeficient (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 Hypmice. The relative inability of PTH to stimulate la-hydroxylase activity is not a function of the hypophosphatemia in the Hypmouse 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 la-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(0H)2D3 caused a comparable reduction of la-hydroxylase activity in normal, Hyp-, and phosphate-depleted normal mice. These observations indicate that the inhibitory control of la-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 la-hydroxylase regulation is manifest in Hyp-mice.

Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

“…The present findings, together with the results ofour earlier reports (4,8), support the hypothesis that enzyme activity in the Hyp-mouse model of XLH is abnormally regulated by factors that influence enzyme function in the PCT. In contrast, enzyme function in the PST is normally modulated.…”

“…In subsequent studies, played a significantly lesser fourfold increment, similar to previously reported observations (8). In contrast, a maximal stimulatory dose of calcitonin (1.25 IU/h) resulted in an identical increase of 25(OH)D-la-hydroxylase activity in both the normals and the mutants, as reported above.…”

“…Despite chronic hypophosphatemia, which is usually associated with increased 1,25-dihydroxyvitamin 1,25(OH)2D, 1,25-dihydroxyvitamin D; PCT, proximal convoluted tubules; PST, proximal straight tubules; PTH, parathyroid hormone; XLH, X-linked hypophosphatemia. 4) as well as impaired response to multiple other stimuli including hypocalcemia and parathyroid hormone (PTH) (5)(6)(7)(8)(9). While these data suggest a generalized defect of renal 25(OH)D-Iahydroxylase in Hyp-mice (and in patients with XLH), recent studies indicate that these observations are insufficient to establish the ubiquity of the derangement.…”

Normal regulation of calcitriol production in Gy mice. Evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.

“…However, these investigations did not include examination of many of the classic biochemical defects characteristic of XLH. In this regard, previous work has established that Hyp mice exhibit abnormal phosphate/PTH regulation of renal 25-hydroxyvitamin D (25[OH]D)-1 a-hydroxylase activity (10)(11)(12)(13). Thus, in the present study we tested for the presence of genetically determined biochemical heterogeneity by examining if Gy mice exhibit disparately regulated calcitriol production.…”

The Journey From Vitamin D–Resistant Rickets to the Regulation of Renal Phosphate Transport

“…Moreover, bone microradiographs from patients with XLH have shown the presence of defective mineralized bone ( Figure 5, C and D), which could reduce PTH-induced release of calcium from bone. PTH administration in Hyp mice also has little effect on 1,25(OH) 2 D levels (72,73).…”