The effects of bone marrow transplantation on X-linked hypophosphatemic mice

The genes responsible for X-linked hypophosphatemic (XLH) vitamin D-resista nt rickets and the murine homolog, hypophosphatemic mice (Hyp), were identi fied as PHEX and Phex (phosphate-regulating gene with homology to endopepti dases on the X chromosome), respectively. However, the mechanism by which i nactivating mutations of PHEX cause XLH remains unknown. We investigated th e mechanisms by syngeneic bone marrow transplantation (BMT) from wild mice to Hyp mice. The expression of the Phex gene was detected in mouse BM cells . BMT introduced a chimerism in recipient Hyp mice and a significant increa se in the serum phosphorus level. The renal sodium phosphate cotransporter gene expression was significantly increased. The effect of BMT on the serum phosphorus level depended on engraftment efficiencies, which represent the dosage of normal gene. Similarly, the serum alkaline phosphatase (ALP) act ivity was decreased and bone mineral density was increased. Furthermore, th e renal expression of 25-hydroxyvitamin D-3 24-hydroxylase, which is a key enzyme in the catabolic pathway and is increased in XLH/Hyp, was improved. From these results, we conclude that transplantation of normal BM cells imp roved abnormal bone mineral metabolism and deranged vitamin D metabolism in Hyp by replacing defective gene product(s) with normal gene product(s). Th is result may provide strong evidence for clinical application of BMT in me tabolic bone disorders.