Pathophysiology of X-Linked Hypophosphatemia, Tumor-Induced Osteomalacia, and Autosomal Dominant Hypophosphatemia: A PerPHEXing Problem

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 have an inactivating 39 deletion of Phex and a phenotype similar to XLH (7–9) secrete factors that inhibit mineralization and renal tubular phosphate transport. Although ADH has many similarities to XLH, mutations of FGF-23, a new member of the growing family of FGF proteins, cause this disorder (5). The biological actions of FGF-23, the mechanisms whereby mutations of FGF-23 influence renal phosphate transport, and the relationship(s) between FGF-23, PHEX, and phosphatonin remain unknown. In particular, evidence has not been presented to ascertain whether FGF-23 has inactivating or activating mutations, directly or indirectly regulates renal phosphate reabsorption in vivo or in vitro, or is a substrate for PHEX. Thus, these new observations do not definitively resolve the mystery of phosphatonin identity and/or prove its existence. In contrast, studies of TIO, which has clinical characteristics similar to both XLH and ADH, have provided additional evidence for a circulating phosphaturic factor (6, 11). White et al. (11), in this issue of JCEM, have contributed to understanding the puzzling pathophysiology of TIO by identifying the presence of FGF-23 in tumors causing this syndrome. This association suggests that this novel member of the FGF family is the phosphaturic factor in TIO, as well as ADH. The related finding that PHEX is also present in tumors from patients with TIO raises the possibility that TIO and XLH (and perhaps ADH) likewise share components of a common pathogenic mechanism. Although the similarities between TIO, ADH, and XLH suggest an overlapping pathophysiology, a plausible unifying hypothesis to explain the etiology of phosphate wasting in these disorders has been difficult to identify. The correct model needs to include at least one enzymatic defect (PHEX protein-substrate) and several putative phosphaturic factors (phosphatonin, FGF-23), as well as demonstrate how the integrated events cause phosphaturia through a mechanism(s) independent of PTH. Furthermore, a fully integrated common pathophysiology for these diseases demands that the characteristic phosphaturia occurs in response to hormonal/metabolic impingement on different points of a common cascade and not on parallel pathways that influence proximal tubular reabsorption of phosphate. In this model phosphatonin, which may be FGF-23 or some other circulating phosphaturic peptide, is a PHEX substrate. As such, either increased production or impaired degradation produces excess phosphatonin. Excessive production of phosphatonin (or FGF-23) in this context overwhelms the function of normal PHEX and explains TIO. In contrast, failure of PHEX to degrade mutant FGF-23 (i.e. phosphatoReceived December 1, 2000. Accepted December 6, 2000. Address correspondence and requests for reprints to: Marc K. Drezner, M.D., Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin Medical School, H4/554 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792-5148. E-mail: mkd@medicine.wisc.edu. 0021-972X/01/$03.00/0 Vol. 86, No. 2 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society