Proximal tubular reabsorption of phosphate is a major determinant of the serum phosphate concentration (1). The presence of many disease states associated with renal phosphate wasting supports the existence of several distinct physiological regulators of renal phosphate transport. Primary and secondary hyperparathyroidism, as well as the hypercalcemia of malignancy syndrome, illustrate the importance of PTH and PTH-related peptide in regulating proximal tubular reabsorption of phosphate (2, 3). More recently, investigation of the hereditary diseases X-linked hypophosphatemia (XLH; Ref. 4) and autosomal dominant hypophosphatemia (ADH; Ref. 5), as well as the acquired hypophosphatemic disorder tumor-induced osteomalacia (TIO; Ref. 6), suggests that novel phosphaturic factors (5, 6) and a newly discovered endopeptidase (4) play a critical role in the regulation of phosphate homeostasis. Indeed, our evolving understanding of the pathogenesis of these diseases dictates that a phosphaturic factor (s) accumulates in the circulation of affected subjects because of (in some cases, endopeptidase mediated) increased production and/or impaired degradation.

Current studies have clearly documented that inactivating mutations of PHEX (4) underlie the pathogenesis of XLH. Although the mechanism (s) by which these mutations influences phosphate transport remains unknown, several investigators have proposed that PHEX metabolizes a putative phosphate-regulating hormone called phosphatonin. According to this hypothesis, secondary to the inability of mutated PHEX to degrade phosphatonin, the putative hormone accumulates, interacts with the kidney, and inhibits phosphate transport. To date, this hormone has not been isolated or cloned, but several groups have measured putative phosphatonin bioactivity in the serum and conditioned medium from osteoblasts of patients and/or animal models harboring inactivating PHEX mutations (7–9). Nevertheless, it remains unclear whether the accumulation of phosphatonin is directly or indirectly related to inactivating Phex mutations. However, this zinc metalloproteinase is expressed predominantly in osteoblasts, in association with genes regulating extracellular matrix production and bone mineralization (10). Moreover, bone is likely a source of phosphatonin and coincidentally osteoblasts derived from hyp-mice, which