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

L. Darryl Quarles and Marc K. Drezner

Departments of Medicine and Pathology Duke University Medical Center Durham, North Carolina and Department of Medicine University of Wisconsin–Madison Madison, Wisconsin 53792-5148

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{at}medicine.wisc.edu


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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, 8, 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 3' deletion of Phex and a phenotype similar to XLH (7, 8, 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. phosphatonin), due to mutations in the substrate, prevents FGF-23 cleavage and causes ADH, whereas XLH results from failure to degrade phosphatonin (or FGF-23) because of inactivating PHEX mutations. The validity of this model, however, rests on the assumption that FGF-23 and/or mutated FGF-23 has phosphaturic actions and is a substrate for PHEX. To date, these requirements have not been documented.

An alternative to this simple enzyme-substrate hypothesis, is a more complex model wherein FGF-23 is not a PHEX substrate, but causes phosphaturia by altering production of the PHEX substrate (i.e. phosphatonin) and/or the activity of PHEX itself. Although recent studies indicate that insulin-like growth factor I administration to rodents enhances renal phosphate reabsorption and increases the level of PHEX messenger RNA, thereby modulating PHEX production (12), at present there is no information regarding FGF-23 regulation of PHEX expression. Thus, there exists no evidence for this more complex model involving alterations in production of phosphatonin by FGF-23 or direct confirmation for a common pathophysiologic mechanism underlying ADH and XLH.

Moreover, additional reported observations do not necessarily reconcile with these models. In this regard, MEPE, or matrix extracellular phosphoglycoprotein, is another candidate for the phosphaturic factor in TIO (6). Rowe et al. (6) recently isolated and cloned this novel matrix protein, which is also expressed in bone marrow, from a complementary DNA expression library derived from the tumors of patients with TIO. Subsequently, others have identified this protein in high concentrations in the majority of tumors from affected patients. Furthermore, MEPE is related to bone-tooth mineral matrix phosphoglycoproteins and has possible PHEX cleavage sites, but definite evidence that MEPE is a substrate for PHEX is lacking. However, unequivocal phosphaturic activity of truncated MEPE has been demonstrated both in vitro and in vivo (unpublished observations). And finally, the expression of MEPE in bone marrow is compatible with other evidence that bone may be involved in the pathogenesis of XLH. In this regard, osteoblasts expressing inactive Phex derived from Hyp mice exhibit an intrinsic defect in mineralization and production of a phosphaturic factor (7). In addition, bone marrow transplantation partially rescues the Hyp mouse phenotype (13), consistent with the presence of MEPE in bone marrow and its potential role in the pathogenesis of XLH. In contrast, FGF-23 is not expressed in bone or bone marrow. These findings raise the possibility that parallel pathways that influence proximal tubular reabsorption of phosphate, rather than a common integrated mechanism, form the pathophysiological basis for TIO, ADH, and XLH.

Furthermore, the discovery of yet additional factors that regulate phosphate homeostasis supports this and perhaps other possibilities, while fueling the puzzlement regarding the pathogenesis of TIO, XLH, and ADH. For example, stanniocalcin 1 (STC1) and 2 (STC2), phosphate-regulating hormones originally isolated from fish (14), respectively stimulate and inhibit renal phosphate reabsorption. Both STCs have been isolated and cloned from a human osteoblast complementary DNA library (unpublished observations) as well as bone (15). STC1 and STC2 are also secreted as phosphoproteins from human fibrosarcoma cells (16). Their role in clinical disorders of phosphate wasting has not been defined. Thus, identification of the phosphaturic factor(s) in XLH, ADH, and TIO, as well as other phosphate wasting disorders, is still a topic of intensive investigations by a number of laboratories.

The existence of such additional factors does not necessarily exclude the possibility that there is an integrated pathophysiology for these disorders. Ascertaining the complexity of the interactions, however, awaits further discoveries. Alternatively, we must consider the possibility that common pathways are not involved in these similar disorders. In this circumstance, TIO, ADH, and XLH may not share an overlapping pathophysiology, but cause renal phosphate wasting through distinct pathways that regulate renal phosphate conservation. Given the existence of FGF-23, MEPE, and STCs, as well as the likely existence of other hormonal regulators of phosphate homeostasis, it is possible that multiple substrates and distinct pathogenic mechanisms underlie TIO, ADH, and XLH. However, the demand that ectopic hormone production by a tumor is commensurate with overproduction of a normally occurring hormone and the similarities in phenotype, particularly between TIO and XLH, argue for commonality in the pathogenesis of these syndromes. Nevertheless, further advances in our knowledge of the biological function(s) of MEPE and FGF-23, as well as identification of PHEX substrates, are essential elements necessary to piece together the pathogenesis of TIO, ADH, and XLH and thereby advance our knowledge of phosphate homeostasis.

Received December 1, 2000.

Accepted December 6, 2000.


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