Correspondence
Fibroblast Growth Factor 23 in Oncogenic Osteomalacia and X-Linked Hypophosphatemia
N Engl J Med 2003; 349:505-506July 31, 2003
- Article
To the Editor:
Jonsson et al. (April 24 issue)1 report that fibroblast growth factor 23 (FGF-23) is markedly elevated in persons with oncogenic osteomalacia or X-linked hypophosphatemia. The authors do not discuss how an elevation in FGF-23 can lead to hypophosphatemia. Renal phosphate reabsorption is a major determinant of the plasma phosphate level and is largely regulated by the type 2 sodium-dependent phosphate cotransporter that is expressed in renal proximal epithelial cells. Yamashita et al.2 found that purified FGF-23 alone could not inhibit sodium-dependent phosphate uptake in a cultured renal proximal epithelial cell line (opossum kidney cells). Thus, FGF-23 might require other molecules for activity or for further processing into its biologically active form. However, FGF-23 with heparin was found to inhibit phosphate uptake significantly, indicating that heparin-like molecules are essential for the activity of FGF-23.2 FGF-23 might not be a direct mediator of impaired regulation of the sodium-dependent phosphate cotransporter. In a recent article, Campos et al.3 reported that FGF-23 is probably a substrate of PHEX protein (which is encoded by PHEX, or phosphate-regulating gene with homologies to endopeptidases on the X chromosome). After the loss of PHEX function, an elevation in FGF-23 could lead to hypophosphatemia in persons with X-linked hypophosphatemia.
3 ReferencesYujiro Kida, M.D., Ph.D.
Tokyo Metropolitan Komagome Hospital, Tokyo 113-8677, Japan1
Jonsson KB ,Zahradnik R ,Larsson T , et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003;348:1656-1663
Full Text | Web of Science | Medline2
Yamashita T ,Konishi M ,Miyake A , et al. Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of mitogen-activated protein kinase pathway. J Biol Chem 2002;277:28265-28270
CrossRef | Web of Science | Medline3
Campos M ,Couture C ,Hirata IY , et al. Human recombinant endopeptidase PHEX has a strict S1' specificity for acidic residues and cleaves peptides derived from fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein. Biochem J 2003;373:271-279
CrossRef | Web of Science | Medline
To the Editor:
FGF-23, recently cloned,1 appears to be a cause of oncogenic osteomalacia. FGF-23 is proteolytically cleaved between the arginine residue at position 179 and the serine residue at position 180, and the processed carboxy- and amino-terminal fragments have no hypophosphatemic action.2 Jonsson et al. found high circulating levels of FGF-23 in patients with oncogenic osteomalacia and X-linked hypophosphatemia by using an enzyme-linked immunosorbent assay (ELISA) that detects a carboxy-terminal portion of FGF-23. Because this ELISA is designed to recognize a synthetic carboxy-terminal fragment, FGF-23(207–244)amide, the measured values seem to represent the total amount of full-length FGF-23 and the inactive carboxy-terminal fragment in the circulation.
We have developed an ELISA that can detect full-length, biologically active FGF-23 with two monoclonal antibodies and have found high levels of FGF-23 in patients with oncogenic osteomalacia and X-linked hypophosphatemia.3 Our results are compatible with those reported by Jonsson et al. and suggest that the ratio of full-length FGF-23 to its carboxy-terminal fragment is relatively constant in these patients. Still, it is possible that the ratio changes in some conditions, and we should be aware that detection of a high FGF-23 level by ELISA for a carboxy-terminal fragment may not always indicate increased activity of FGF-23.
3 ReferencesSeiji Fukumoto, M.D., Ph.D.
University of Tokyo Hospital, Tokyo 113-8655, Japan
fukumoto-tky@umin.ac. jp Takeyoshi Yamashita, Ph.D.
Kirin Brewery, Takasaki 113-8655, Japan1
Shimada T ,Mizutani S ,Muto T , et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001;98:6500-6505
CrossRef | Web of Science | Medline2
Shimada T ,Muto T ,Urakawa I , et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002;143:3179-3182
CrossRef | Web of Science | Medline3
Yamazaki Y ,Okazaki R ,Shibata M , et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 2002;87:4957-4960
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Kida and Drs. Fukumoto and Yamashita provide important comments regarding our findings with the use of a “sandwich” assay that detects intact FGF-23 as well as a carboxyl-terminal fragment. It is now well established that FGF-23, when given to animals, causes changes in phosphate homeostasis and vitamin D metabolism that are similar to those observed in oncogenic osteomalacia and X-linked hypophosphatemia. Because of these data from experiments in vivo and the finding that FGF-23 is readily detectable in plasma or serum from healthy persons, it appears likely that this protein has a pivotal role in phosphate homeostasis. However, the mechanisms through which phosphate homeostasis is affected by FGF-23 remain uncertain, particularly since studies exploring its effect on phosphate transport in opossum kidney cells and the effect of cleavage by PHEX have been conflicting.1-3
Our observation that about two thirds of the patients with X-linked hypophosphatemia in our study had increased levels of carboxy-terminal FGF-23 suggests new insights into the role of PHEX in the cleavage of intact FGF-23. Drs. Fukumoto and Yamashita point out that their FGF-23 assay, which presumably detects only intact FGF-23, yielded similar results.4 If the data are confirmed in a larger series of patients with X-linked hypophosphatemia, the results could suggest that the two assays are of similar clinical utility. However, since the epitopes of the antibodies used in the assay of “intact” FGF-23 remain to be defined further, it is also conceivable that the two assays detect similar or identical, as yet undefined FGF-23 fragments that are normally cleaved by PHEX.
Exploring the regulation of phosphate homeostasis through FGF-23 remains challenging, and further work is required. Cell-based systems to assess the biologic activity of FGF-23 need to be improved, PHEX-dependent cleavage of FGF-23 needs to be studied in more detail, and intact FGF-23 and its fragments (biologically active or inactive) need to be measured in patients with oncogenic osteomalacia, X-linked hypophosphatemia, and autosomal dominant hypophosphatemic rickets. The two available assays for FGF-23 will help in each of these important efforts. However, once FGF-23 cleavage by PHEX is better understood, it may well be necessary to develop additional assays that specifically detect the cleavage products as well as assays that detect the full-length substrate.
4 ReferencesKenneth Jonsson, M.D., Ph.D.
University of Uppsala, SE-751 85 Uppsala, SwedenMichael Econs, M.D.
Indiana University School of Medicine, Indianapolis, IN 46202Harald Jüppner, M.D.
Massachusetts General Hospital, Boston, MA 02114
jueppner@helix.mgh. harvard. edu 1
Bowe A ,Finnegan R ,Jan de Beur S , et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun 2001;284:977-981
CrossRef | Web of Science | Medline2
Guo R ,Liu S ,Spurney R ,Quarles LD . Analysis of recombinant Phex: an endopeptidase in search of a substrate. Am J Physiol Endocrinol Metab 2001;281:E837-E847
Web of Science | Medline3
Campos M ,Couture C ,Hirata IY , et al. Human recombinant endopeptidase PHEX has a strict S1' specificity for acidic residues and cleaves peptides derived from fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein. Biochem J 2003;373:271-279
CrossRef | Web of Science | Medline4
Yamazaki Y ,Okazaki R ,Shibata M , et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 2002;87:4957-4960
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Seiji Fukumoto, Takeyoshi Yamashita. (2007) FGF23 is a hormone-regulating phosphate metabolism—Unique biological characteristics of FGF23. Bone 40:5, 1190-1195
CrossRef
