X-linked hypophosphatemia (vitamin D-resistant rickets) is a human and mouse disease caused by a mutant dominant gene on the X-chromosome. One principal defect is impaired renal tubular reabsorption of phosphate which leads to increased urinary phosphate and reduced plasma phosphate. There are also reports of intestinal malabsorption of calcium and phosphate in children but not adults with this disease. In addtion there is intestinal malabsorption of calcium and low intestinal vitamin D-dependent calcium binding protein in young X-linked hypophosphatemic (Hyp) mice. This malabsorption of calcium occurs in close correlation with the failure of skeletal mineralization. Nursing pups and adult mice absorb calcium normally from the intestine and accumulate mineral at a normal rate in their skeleton. It is the young, rapidly growing mice after weaning which malabsorb calcium and which fail to increase in total body calcium or femur ash weight. The bone disease of X-linked hypophosphatemia may have more than one cause, and intestinal malabsorption of calcium may be a major contributor to the pathogenesis of the bone disease. To test this hypothesis we will bypass the intestinal malabsorption and deliver additional calcium to the skeleton. Whether this ameliorates the bone disease will be measured. We will further investigate the nature of intestinal malabsorption by measuring the saturable and the diffusional components of calcium absorption in Hyp mice (and normal controls) before, during and after this period of intestinal malabsorption. We will investigate the cause of the malabsorption by measuring intestinal 1,25-(OH)2-vitamin D receptor occupancy in vivo and by seeking further proof of the identification of the endogenous plasma 1,25-(OH)2-vitamin D. 1,25-(OH)2-vitamin D also stimulates the kidneys to produce calcium binding proteins and the bone to make bone G1a protein. We will examine these other target organs of the Hyp mice to test whether they also fail to respond to their endogenous 1,25-(OH)2-vitamin D. Current therapy for this disease in humans is based on the theory that the renal phosphate leak is the only pathogenic mechanism. If intestinal malabsorption of calcium can be shown to be a significant pathogenic mechanism as well, it will suggest the need for novel therapies aimed at this defect. Such therapies will improve patient health by leading to a better normalization of bone growth in afflicted children.
