Background Mutations in fibroblast growth factor 23 (FGF-23)cause autosomal dominant hypophosphatemic rickets. Clinicaland laboratory findings in this disorder are similar to thosein oncogenic osteomalacia, in which tumors abundantly expressFGF-23 messenger RNA, and to those in X-linked hypophosphatemia,which is caused by inactivating mutations in a phosphate-regulatingendopeptidase called PHEX. Recombinant FGF-23 induces phosphaturiaand hypophosphatemia in vivo, suggesting that it has a rolein phosphate regulation. To determine whether FGF-23 circulatesin healthy persons and whether it is elevated in those withoncogenic osteomalacia or X-linked hypophosphatemia, an immunometricassay was developed to measure it.
Methods Using affinity-purified, polyclonal antibodies against[Tyr223]FGF-23(206–222)amide and [Tyr224]FGF-23(225–244)amide,we developed a two-site enzyme-linked immunosorbent assay thatdetects equivalently recombinant human FGF-23, the mutant formin which glutamine is substituted for arginine at position 179(R179Q), and synthetic human FGF-23(207–244)amide. Plasmaor serum samples from 147 healthy adults (mean [±SD]age, 48.4±19.6 years) and 26 healthy children (mean age,10.9±5.5 years) and from 17 patients with oncogenic osteomalacia(mean age, 43.0±13.3 years) and 21 patients with X-linkedhypophosphatemia (mean age, 34.9±17.2 years) were studied.
Results Mean FGF-23 concentrations in the healthy adults andchildren were 55±50 and 69±36 reference units(RU) per milliliter, respectively. Four patients with oncogenicosteomalacia had concentrations ranging from 426 to 7970 RUper milliliter, which normalized after tumor resection. FGF-23concentrations were 481±528 RU per milliliter in thosewith suspected oncogenic osteomalacia and 353±510 RUper milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia.
Conclusions FGF-23 is readily detectable in the plasma or serumof healthy persons and can be markedly elevated in those withoncogenic osteomalacia or X-linked hypophosphatemia, suggestingthat this growth factor has a role in phosphate homeostasis.FGF-23 measurements might improve the management of phosphate-wastingdisorders.
Mutations in the gene encoding fibroblast growth factor 23 (FGF-23)(Online Mendelian Inheritance in Man [OMIM] number 605380) causeautosomal dominant hypophosphatemic rickets (OMIM number 193100).1As is consistent with a presumed role in phosphate homeostasis,FGF-23 messenger RNA (mRNA) and protein are markedly overexpressedin tumors that are responsible for oncogenic osteomalacia,2,3,4and recombinant FGF-23 induces hypophosphatemia in vivo as aresult of urinary phosphate wasting.3,5,6
FGF-23 is initially produced as a 251-amino-acid precursor,with residues 1 through 24 serving as signal peptide that allowsefficient secretion of the mature protein.1,3,7 Tumors responsiblefor oncogenic osteomalacia and cells expressing wild-type FGF-23produce at least two molecular forms of FGF-23 (the full-length,32-kD protein and a 12-kD fragment). Since only the larger fragmentis present in cells carrying one of the FGF-23 missense mutationsidentified in autosomal dominant hypophosphatemic rickets,2,3,6,8it has been proposed that these mutations affect sites of cleavageby a furin-type proprotein convertase (an endoprotease thatcleaves protein precursors after pairs of basic residues). Thus,the mutations would impair FGF-23 degradation and thereby enhanceor prolong its biologic activity.3,6,8,9,10
In addition to being a substrate for furin-type enzymes, FGF-23may also be a substrate for PHEX (the phosphate-regulating proteinwith homologies to endopeptidases encoded by a gene on the Xchromosome), which is mutated in patients with X-linked hypophosphatemicrickets (OMIM number 307800).9,11,12 Different molecular mechanisms— overproduction of FGF-23 by the tumors responsible foroncogenic osteomalacia,2,3 generation of a mutant FGF-23 thatis resistant to cleavage by furin-type enzymes,2,3,6,8,10 andimpaired FGF-23 degradation due to reduction or loss of PHEXactivity9 — may thus lead to elevated FGF-23 concentrationsand consequently to urinary phosphate wasting.
To explore the role of FGF-23 in the regulation of phosphatehomeostasis, we developed a two-site enzyme-linked immunosorbentassay (ELISA) that detects the carboxy-terminal portion of FGF-23,and we measured the circulating concentrations of this growthfactor in healthy persons and in patients with oncogenic osteomalaciaor X-linked hypophosphatemia.
Methods
Peptide Synthesis and Antibody Production
Peptides were synthesized by the Biopolymer Core Facility, MassachusettsGeneral Hospital, Boston. Peptides representing portions ofthe FGF-23 precursor — [Cys70]FGF-23(51–69)amide,[Tyr185] FGF-23(186–206)amide, [Tyr223]FGF-23(206–222)amide,and [Tyr224]FGF-23(225–244)amide — were coupledto keyhole limpet hemocyanin, emulsified with complete Freund'sadjuvant, and used for subcutaneous immunization of eight goats(with approximately 100 µg per animal); each peptide wasinjected into two animals. Subsequent booster injections (approximately50 µg per animal) were performed every four weeks withpeptides emulsified with incomplete Freund's adjuvant. Eachpeptide was covalently coupled to agarose (AminoLink Kit, PierceChemical), and 30-to-200-ml quantities of each crude polyclonalantiserum were affinity-purified with the use of the appropriateimmobilized peptide, as previously described.13
Generation of Recombinant FGF-23
The complementary DNA (cDNA) encoding full-length human FGF-23was amplified by the polymerase chain reaction from a cDNA libraryderived from a previously described oncogenic osteomalacia tumor.2To express recombinant FGF-23, the polymerase-chain-reactionproduct was ligated into the vector pIZ/V5-His (InsectSelectcloning kit, Invitrogen) to yield a plasmid called [V5-His]rhFGF-23(1–251);the two epitope tags were located at the carboxy-terminal endof the encoded FGF-23; the nucleotide sequence of the constructwas then confirmed by sequence analysis. Sf-9 insect cells,which allow high-level protein expression, were then transfected(Insectine-Plus transfection reagent, Invitrogen) with the [V5-His]rhFGF-23(1–251) plasmid. The transfected cells were maintainedat 25°C and selected for resistance to Zeocin, an antibioticof the bleomycin family (300 µg per milliliter, Invitrogen).Polyclonal cell lines with high levels of [V5-His]rhFGF-23(1–251)expression were expanded and maintained in 250-ml spinner flaskswith serum-free insect medium (Trichoplusia ni Medium FormulationHink [TNF-FH], GIBCO) supplemented with Zeocin (50 µgper milliliter) and a combination of amphotericin B, penicillin,and streptomycin. Conditioned medium from stably transfectedcells expressing mature, [V5-His]–tagged FGF-23 and the[V5-His]–tagged carboxyl-terminal fragment (collectivelyreferred to as [V5-His] rhFGF-23) was collected every otherday and kept at –20°C until use. Bacterially produced[V5-His]rhFGF-23(25–251) protein, the mutant protein inwhich glutamine is substituted for arginine at position 179([V5-His;R179Q]rhFGF-23(25–251)), and fibroblast growthfactor 19 were kindly provided by Drs. Susan Schiavi and MarlonPragnell (Genzyme).
Development of an ELISA for the Detection of FGF-23
Eight affinity-purified antibodies were immobilized on microtiter-platewells and biotinylated for subsequent detection with horseradishperoxidase conjugated to avidin (Pierce Chemical) to test differentcombinations of capture and detection antibodies in a two-siteELISA. The best recognition and sensitivity for the detectionof [V5-His]rhFGF-23 were observed when anti–[Tyr-223]FGF-23(206–222)amidewas used as a capture antibody and anti–[Tyr-224]FGF-23(225-244)amidewas used as a detection antibody. In the assay, 150 µlof recombinant or synthetic FGF-23 or unknown sample and 50µl of biotinylated detection antibody were used in eachmicrotiter-plate well. After mixing and incubation for 18 to24 hours at room temperature, the wells were rinsed five timeswith normal saline containing 0.05 percent Tween 20 (350 µlper well), and the immobilized "sandwich" complex was then incubatedwith horseradish peroxidase–conjugated avidin (200 µl)in the dark for 1 hour to allow the enzyme–avidin complexto bind to the biotinylated antibody. After rinsing (with 350µl per well, five times), the enzyme bound to the wellswas incubated in the dark with tetramethylbenzidine substratesolution (200 µl) for 30 minutes and immediately measuredin a spectrophotometric plate reader at 620 nm. The reactionwas then stopped by the addition of 1 M sulfuric acid (50 µlper well); after brief mixing, the plate was again read at 450nm. This approach, involving dual reading at 620 and 450 nm,ensured that the assay had a wide dynamic range (3 to 2300 RUper milliliter).
Study Subjects
To derive a reference range, blood samples (plasma in EDTA orserum) were collected from 85 healthy women and 62 healthy men(mean [±SD] age, 48.4±19.6 years) and 26 children(mean age, 10.9±5.5 years) with normal serum calciumand phosphate concentrations and normal renal function. Thesamples were obtained after the subjects had fasted overnight,and all the measurements were made from the same blood-samplecollection. The study was approved by the human-studies committeesof the Massachusetts General Hospital, Indiana University Schoolof Medicine, St. Thomas' Hospital, National Hyogo-Chuo Hospital,and the University of Uppsala. Written or oral informed consentwas obtained before the samples were collected.
Seventeen patients with confirmed or suspected oncogenic osteomalaciawere studied (Table 1). Patients 1, 3, and 6 have been previouslydescribed,2,14 and the measurements were performed on storedsamples. In five of the patients with confirmed oncogenic osteomalacia,samples were obtained for measurement of FGF-23 before and aftersurgical removal of the tumor2,14; in one patient, whose diseasewas cured after tumor resection, only a preoperative samplewas available. Oncogenic osteomalacia was suspected in 11 patientson the basis of clinical, radiologic, and laboratory findings,but a tumor had not been identified. The diagnosis of X-linkedhypophosphatemia was based on a consistent medical history,a positive family history (in some cases), findings on physicalexamination, radiologic evidence of childhood rickets, and hypophosphatemiadue to increased renal losses, as indicated by diminished tubularreabsorption of phosphate (Table 1), with initially normal serumconcentrations of calcium and parathyroid hormone and normalconcentrations of other serum electrolytes. All the patientswith X-linked hypophosphatemia except one (Patient 37) weretreated with oral phosphate and 1,25-dihydroxyvitamin D.
Table 1. Laboratory Findings in Patients with Documented or Suspected Oncogenic Osteomalacia and in Patients with X-Linked Hypophosphatemia.
Results
Characteristics and Performance of the FGF-23 Immunoassay
An immunometric assay for detecting the carboxy-terminal portionof FGF-23 was established with an affinity-purified antibodyraised against [Tyr223]-FGF-23(206–222)amide as a captureantibody and an affinity-purified biotinylated antibody raisedagainst [Tyr224]FGF-23(225–244)amide as a detection antibody(Figure 1A). Since no synthetic or natural (purified) full-lengthFGF-23 is available, dilutions of supernatant from Sf-9 cellsexpressing [V5-His]-rhFGF-23 were used as a standard. The concentrationsof standards and controls are expressed in reference units (RU)per milliliter relative to a specific lot of conditioned cell-culturemedium (Figure 1B) (available on request from Dr. Jüppner).
Figure 1. Characteristics of the Two-Site Enzyme-Linked Immunosorbent Assay for Fibroblast Growth Factor 23.
Panel A shows the amino acid sequence of human fibroblast growth factor (FGF-23). The putative signal peptide (residues 1 to 24) is shown on a shaded background; the amino acid sequence of the predicted mature protein is shown without shading; the amino acid sequence of synthetic FGF-23(207–244)amide is shown in bold type; and the sequences that were used for immunization are underlined. Either Tyr223 or Tyr224 was added to the peptides used for immunization. As shown in Panel B, microtiter-plate wells were coated with anti–[Tyr223]FGF-23(206–222)amide as a capture antibody. The plates were then incubated with increasing concentrations of [V5-His]rhFGF-23 (green squares), serial dilutions of [V5-His;R179Q]rhFGF-23(25–251) (blue circles), or FGF-23(207–244)amide (red triangles). After extensive rinsing, the biotinylated detection antibody directed against [Tyr - 224]FGF-23(225–244)amide was added for quantification with horseradish peroxidase–conjugated avidin. Recombinant fibroblast growth factor 19, at concentrations as high as 1.8 µg per milliliter, was not detected (data not shown). Panel C shows increasing concentrations of [V5-His]rhFGF-23 (green squares) and serial dilutions of serum from Patients 2 (red triangles) and 10 (purple triangles). In Panels B and C, the I bars represent standard deviations.
The sensitivity of the assay, 3.0 RU per milliliter, was determinedby the 95 percent confidence limit (±2 SD) in 20 duplicatedeterminations of the standard (0 RU per milliliter). The intraassayvariation was less than 5.0 percent, and the interassay variationless than 7.3 percent. Blood samples, collected either as plasma(in EDTA or heparin) or as serum, showed no appreciable differencesin the detectable concentration of immunoreactive FGF-23 (datanot shown). Serial dilutions of samples from two patients withoncogenic osteomalacia showed parallelism to the standard curve(Figure 1C). Studies in which [V5-His]rhFGF-23 was added toserum or plasma samples from healthy persons yielded recoveriesof 89 to 115 percent. [V5-His]rhFGF-23 from Sf-9 cells and [V5-His]rhFGF-23(25–251)from bacterial cultures (data not shown), [V5-His;R179Q]rhFGF-23(25–251)from bacterial cultures, or synthetic FGF-23(207–244)amideshowed parallel dose dilutions (Figure 1B). Recombinant humanfibroblast growth factor 19 at concentrations of up to 1.8 µgper milliliter showed no cross-reactivity (data not shown).
Circulating FGF-23 Concentrations in Healthy Persons and in Patients with Phosphate-Wasting Disorders
Samples from the 147 healthy adults with normal concentrationsof calcium, phosphate, and creatinine revealed mean FGF-23 concentrationsof 55±50 RU per milliliter (52.9±20.8 RU per milliliterin women and 42.0±15.8 RU per milliliter in men) (Figure 2).The mean concentrations in samples from the 26 healthy childrenwere 69±36 RU per milliliter, and samples taken everyfour hours during the day (8 a.m., noon, 4 p.m., and 8 p.m.)from six healthy adults eating a regular diet revealed no majordifferences in mean FGF-23 concentrations (35±4.1, 44±6.6,35±14.6, 77±17.0, 58±5.3, and 42±7.6RU per milliliter for each adult, respectively). The 10 patientswith end-stage renal disease who were undergoing dialysis hadelevated levels of FGF-23 (range, 162 to 5820 RU per milliliter);dilutions of these samples ran parallel to the standard curve.
Figure 2. Circulating Concentrations of Fibroblast Growth Factor 23 (FGF-23) in Patients with Phosphate-Wasting Disorders.
The graph shows the concentrations of FGF-23 in patients with confirmed or suspected oncogenic osteomalacia before and after surgery and in patients with X-linked hypophosphatemia treated with oral phosphate and 1,25-dihydroxyvitamin D. Only Patient 37 (open triangle) was not receiving treatment when FGF-23 was measured. The shaded area represents the normal range of FGF-23 concentrations (means ±2 SD), which is based on measurements in 147 healthy adults (mean [±SD] age, 48.4±19.6 years) and which is not different from that of 26 children (mean age, 10.9±5.5 years).
As indicated in Table 1, six patients with oncogenic osteomalaciahad complete resolution of renal phosphate wasting and consequentnormalization of phosphate concentrations in the blood aftertumor resection. Before tumor resection, five of these patientshad markedly elevated FGF-23 concentrations (Figure 2); aftertumor removal, their FGF-23 concentrations were within or slightlyabove the normal range. Patient 4, who had oncogenic osteomalacia,had FGF-23 concentrations well within the range for healthycontrols before and after surgery (Table 1), although removalof the tumor led to normalization of urinary phosphate excretionand serum phosphate concentrations. Of samples from 11 otherpatients with suspected oncogenic osteomalacia, the FGF-23 concentrationswere elevated in 8 but normal in 3.
Thirteen of the 21 patients with X-linked hypophosphatemia (meanage, 34.9±17.2 years) had elevated FGF-23 concentrations(>155 RU per milliliter [2 SD above the mean for healthyadults]) (Figure 2). The eight patients with X-linked hypophosphatemiaand normal FGF-23 values had serum phosphate concentrationswell below the reference range (Table 1).
Discussion
The ELISA for FGF-23 that was developed and clinically evaluateddetects full-length FGF-23 as well as a synthetic carboxyl-terminalfragment, FGF-23 (207–244)amide. Because two affinity-purifiedantibodies were raised against synthetic FGF-23 fragments, thisassay does not detect fibroblast growth factor 19, a memberof the fibroblast growth factor family of proteins that is moreclosely related to FGF-23 than other fibroblast growth factors.Furthermore, the substitution of glutamine for arginine at position179 of [V5-His]rhFGF-23(25–251) did not alter cross-reactivity,making it likely that this assay can detect wild-type FGF-23and the mutant forms identified in autosomal dominant hypophosphatemicrickets1,2,10 with equal efficacy. However, in patients withvarious phosphate-wasting disorders, fragments of FGF-23 inaddition to full-length wild-type and mutant forms of protein2,3,8,10may exist in the circulation, and the fragments may have alteredaffinity for one or both of the two antibodies. In our study,circulating FGF-23 concentrations were readily detectable inhealthy adults and children, increasing the likelihood thatthis growth factor may be involved in the physiologic regulationof phosphate homeostasis. However, FGF-23 expression could bedetected only at low levels and only in a few tissues,1,2,3,7and its normal source in healthy persons therefore remains uncertain.
In oncogenic osteomalacia, tumor tissue is the major sourceof FGF-23, as previously shown by the abundant amounts of FGF-23mRNA and protein produced by these often remarkably small andhard-to-find tumors.2,3,4,15 In some cases, elevated FGF-23concentrations normalized after tumor removal — an observationthat suggests that the ELISA for FGF-23 might be a useful toolfor locating occult FGF-23–producing tumors through selectivevenous sampling and for monitoring the surgical or medical treatmentof patients with this disorder.15
Patient 4, who had oncogenic osteomalacia, had concentrationsof FGF-23 well within the normal range both before and afterthe removal of his tumor, although his urinary phosphate excretionand, consequently, his serum phosphate concentration normalizedafter resection. The tumor from this patient expressed FGF-23mRNA, as determined by the reverse-transcriptase polymerasechain reaction, but it is currently unknown whether the mRNAwas as abundantly expressed as in previously reported cases.2,3,4,15Thus, it remains uncertain whether FGF-23 or other proteinswith phosphaturic activity could be responsible for the diseasein this and possibly other patients.
No attempts were made to measure FGF-23 in patients with X-linkedhypophosphatemia after the discontinuation of regular medication,since the half-life of FGF-23 is currently unknown and sinceprolonged withdrawal of therapy might affect patient outcomes.However, the finding that FGF-23 is elevated in some, but notall, patients with X-linked hypophosphatemia may have implicationsfor our current understanding of this genetic disorder.
The FGF-23 assay may facilitate studies that address the roleof FGF-23 in normal phosphate homeostasis and that explore whetheradditional molecular species of this growth factor are presentin the circulation of healthy persons and of patients with phosphate-wastingdisorders or various stages of renal failure. FGF-23 measurementsmay thus offer improved insight into the normal regulation ofphosphate homeostasis and have implications for the diagnosisand treatment of phosphate-wasting disorders.
Supported in part by grants from the National Institutes ofHealth (DK46718 to Dr. Jüppner, AR42228 and K24-AR02095to Dr. Econs, and DK063934-01 to Dr. White), the Swedish ResearchCouncil, the Swedish Foundation for International Cooperationin Research and Higher Education, and Stiftelsen Tore Nilsson.
Dr. Jüppner reports having received honorariums from Genzymeand having received patents on parathyroid hormone and parathyroidhormone–related peptide (PTH/PTHrP) receptors and on PTH/PTHrPanalogues activating these receptors. Drs. White and Econs reporthaving a patent pending on FGF-23.
We are indebted to Drs. Shoichi Natori and Ken Arai (Aso-IzukaHospital); Sizu Suzuki, Toshihiko Yanase, and Hajime Nawata(Kyushu University); Seiki Wada (Saitama Medical School); AkiraKanazawa (Tokyo Medical College); Masaaki Inaba, Kiyoshi Nakatsuka,and Yoshiki Nishizawa (Osaka City University); Naomitsu Kuwamura(Amagasaki Hospital); Takeshi Sugishita, Takuo Fujita, and KazuoChihara (Kobe University) — all in Japan; and John T.Crawford (Massachusetts General Hospital, Boston) — allof whom provided samples and helpful discussion.
Source Information
From the Endocrine Unit, Department of Medicine, and MassGeneral Hospital for Children, Massachusetts General Hospital and Harvard Medical School, Boston (K.B.J., H.J.); the Departments of Surgical Sciences (K.B.J., T.L.) and Medical Sciences (O.L.), University of Uppsala, Uppsala, Sweden; Immutopics, San Clemente, Calif. (R.Z., J.L.); the Departments of Medicine and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis (K.E.W., M.J.E.); the Division of Endocrinology and Metabolism, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (T.S., A.M.); the Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine (Y.I.), the Department of Pediatrics, Minoh City Hospital, and the Department of Pediatrics, Osaka University Graduate School of Medicine (T.Y.) — all in Osaka, Japan; the Department of Chemical Pathology, St. Thomas' Hospital, London (G.H.); the Division of Endocrinology and Metabolism, Department of Medicine, Hyogo Prefectural Amagasaki Hospital, Hyogo, Japan (H.K.); the Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University and Aso-Iizuka Hospital, Fukuoka, Japan (K.O.); the Department of Internal Medicine, Kuyunghee University, Seoul, Korea (I.M.Y.); and National Hyogo-Chuo Hospital, Sanda Hyogo, Japan (A.M.).
Address reprint requests to Dr. Jüppner at the Endocrine Unit, Wellman 5, Massachusetts General Hospital, Boston, MA 02114, or at jueppner{at}helix.mgh.harvard.edu.
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