The quest for circulating phosphaturic factor(s) has made a major advance with the recognition that an FGF family member, FGF-23, is encoded by the gene mutated in ADHR (2
) and made resistant to endopeptidase degradation by the missense mutations underlying the disease (3
). The detection of high levels of FGF-23 mRNA and protein in most TIO-causing tumors and of FGF-23 in the serum of patients with TIO (8
) suggests that FGF-23 may be seen as a circulating phosphaturic factor of potentially broader significance. While additional factors, such as MEPE (10
) or secreted FRP-4 (11
), have been proposed as potential regulators of renal phosphate handling, strong experimental evidence has been provided in animal models for the potential role of FGF-23 as a phosphaturic factor (12
). A phosphate-wasting syndrome resembling TIO (24
) and localized mineralization defects (25
) occur in a substantial proportion of patients with FD. A clear-cut picture of generalized, overt hypophosphatemic osteomalacia is also observed in rare cases of this disorder (21
). We therefore analyzed the tissue source, serum levels, and effect on renal phosphate handling of FGF-23 in FD.
We have demonstrated that FGF-23 mRNA is expressed in FD tissue, predominantly by cells of osteogenic lineage comprising the so-called fibrosis characteristic of the lesion and the abnormal osteoblasts and osteocytes associated with the dysplastic bone trabeculae. Production of FGF-23, by lesional tissue and by cells derived from it, is reflected by serum levels that are significantly higher in FD patients than in normal controls and correlate inversely with phosphatemia and renal phosphate reabsorption in FD patients. These data support the notion that FGF-23 may act as a phosphaturic factor in FD and may explain the occurrence of localized (lesional) or generalized mineralization defects in the skeleton of some FD patients.
Our studies, however, also reveal aspects of the relationships between FGF-23 and phosphate metabolism that are unique to FD and in turn highlight novel facets of the pathophysiology of FGF-23 and phosphate metabolism at large. We have shown that FGF-23 mRNA is expressed in normal bone cells, and it is produced in culture by FD and normal bone-derived cells, as well as by wild-type and GNAS1
-mutated cells, at apparently similar levels. These data indicate that skeletal cells represent a previously unrecognized physiological source of FGF-23 and that production of FGF-23 by FD cells cannot be accounted for as a consequence of the GNAS1
mutations, but rather reflect their osteogenic nature (28
). Likewise, the detection of abnormally high levels of serum FGF-23 in FD patients and the occurrence of a renal phosphate–wasting syndrome cannot be explained solely by the development of a clone of GNAS1
-mutated cells in the body, which would produce inappropriate levels of FGF-23. This is in keeping with the observation that renal phosphate wasting is not an obligate occurrence in FD patients, all of whom harbor some mutated FD osteogenic cells in their skeletal lesion(s), but rather occurs in only approximately 50% of FD patients. As we have shown, patients with renal phosphate wasting are characterized by a high disease burden. On the other hand, serum levels of FGF-23 are not significantly elevated in patients with FD who are free of a phosphate-wasting syndrome. These patients, as we have shown, are characterized by a significantly lower disease burden. Thus, clinical observations are easily reconciled with, and in fact explained by, the lack of major differences between normal and FD cells when FGF-23 production is evaluated at the single cell level. In addition, the observation that disease burden significantly correlates with serum FGF-23 and serum phosphate and urinary deoxypyridinoline levels in FD patients fits well with the observed incidence of phosphate wasting in patients with more extensive disease.
Current views of the role of FGF-23 in phosphate metabolism inscribe both inherited and acquired phosphaturic disorders into a common paradigm (39
). Excess circulating FGF-23 is postulated to represent a final common pathway of XLH, ADHR, and TIO. In XLH and ADHR, the excess bioactive FGF-23 would result from lack of adequate degradation, either due to lack of a putative degrading enzyme activity (in XLH) or to gain-of-function mutations resulting in reduced degradability of FGF-23 itself (in ADHR). In this scheme, TIO would represent a situation of inappropriate, and possibly ectopic, production of excess FGF-23 by the so-called phosphaturic tumors. By comparing the serum levels of FGF-23 observed in FD patients in our study with those recently reported for patients with TIO (38
), it is notable that several kilograms of FD tissue (as reflected by disease burden) are required to generate serum levels of FGF-23 equivalent to that which is generated by tumors that often do not exceed the size of 1 cm and are mostly benign. This implies marked differences in the local regulation of expression and metabolism of FGF-23 in FD (cells) versus phosphaturic tumor (cells), which are, as yet, not well understood. In the general scheme of phosphaturic disorders associated with excess bioactive FGF-23, however, FD represents a novel scenario, somewhat distinct from the one represented by TIO. In TIO, excess levels of serum FGF-23 are generated by an abnormally high release of the factor at the single cell level (inappropriate cellular production). In FD, an excess of osteogenic cells, normally competent to release FGF-23, accumulate in fibrous dysplastic tissues (28
) (inappropriate amount of cells normally producing FGF-23).
In summary, our results provide direct evidence for the production of FGF-23 by normal, active osteogenic cells, and by osteogenic cells in fibrous dysplastic lesions, for elevated levels of circulating FGF-23 in FD patients and for their relationship to an associated state of renal phosphate wasting and hypophosphatemia. These data provide a novel insight into mechanisms underlying the more (hypophosphatemic rickets; refs. 21
) and less (localized intralesional osteomalacia; ref. 25
) conspicuous consequences of renal phosphate wasting in FD that are increasingly recognized as an important determinant of skeletal disease severity (26
). In addition, they extend the range of human disorders for which FGF-23 is clinically and biologically relevant as a candidate for a circulating phosphaturic factor and the range of pathophysiological mechanisms leading to excess circulating bioactive FGF-23. Finally, they raise the interesting possibility that bone cells themselves may act as an endocrine organ regulating systemic phosphate metabolism.