Our proposed studies are designed to investigate the role of abnormal vitamin D metabolism and/or parathyroid hormone secretion in the pathogenesis of X-linked hypophosphatemic rickets and to determine the mechanism for the impaired renal tubular reabsorption of phosphate characteristic of this disease. Studies of potential abnormalities in vitamin D metabolism will be conducted in both affected human subjects and in the murine homologue of the disease (Hyp-mice). In these investigations we will determine the circulating concentration of vitamin D metabolites before and after hormonal and/or metabolic perturbations which normally affect the production of 1,25(OH)2D and/or 24,25(OH)2D. In addition we will directly assay 25(OH)D-1Alpha-(and 24R-) hydroxylase activity in the Hyp-mouse kidney to determine whether hormonal/metabolic regulation of vitamin D metabolism remains intact. In complementary studies we will test the therapeutic efficacy of specific drug regimens on the bone lesions and biochemical abnormalities characteristic of X-linked hypophosphatemic rickets. Investigation of potential abnormalities in parathyroid hormone will be accomplished by measuring bioactive hormone in affected humans and Hyp-mice in response to hypo- and hypercalcemic stimuli. In addition, we will assess the integrity of the calcium transducing mechanism in Hyp-mouse parathyroid tissue, in vitro. In experiments designed to investigate the mechanism(s) of impaired renal tubular phosphate reabsorption, we plan a series of in vitro experiments utilizing Hyp-mouse kidney. Specific emphasis will be directed at determining whether abnormalities of the cyclic AMP-phosphorylatable substrate in the apical membranes of Hyp-mouse kidneys underlie the defect in phosphate transport. Our studies should provide important data relative to the cause of, and therapy for, X-linked hypophosphatemic rickets.
