REVIEW URRENT C OPINION
Anti-fibroblast growth factor 23 antibody therapy Seiji Fukumoto
Purpose of review The review is intended to provide an update on the expanding knowledge regarding diseases caused by the excess actions of fibroblast growth factor 23 (FGF23) and also on the new therapeutic measures for these diseases, with an emphasis on the anti-FGF23 antibody. Recent findings FGF23 decreases serum phosphate and 1,25-dihydroxyvitamin D levels. After the cloning of FGF23, several hypophosphatemic diseases, including tumor-induced osteomalacia and X-linked hypophosphatemic rickets (XLHR), were shown to be caused by excess actions of FGF23. In addition, recent studies indicated that mutations in the family with sequence similarity 20, member C (FAM20C), HRAS and NRAS genes, also caused FGF23-related hypophosphatemic diseases. The inhibition of FGF23 production or activity is, theoretically, an ideal treatment for these hypophosphatemic diseases. The C-terminal fragment of FGF23, inhibitors of FGF receptor and extracellular signal-regulated kinase, and anti-FGF23 antibody were shown to inhibit FGF23 actions both in vitro and in vivo. A phase I clinical trial of anti-FGF23 antibody has shown that this antibody increases serum phosphate in patients with XLHR. Summary These recent findings confirm that FGF23 has a pivotal role in phosphate metabolism. The inhibition of FGF23 production or activity is promising as a new therapy for FGF23-related hypophosphatemic diseases. Further studies are clearly necessary to establish the clinical utility and long-term safety of these measures. Keywords extracellular signal-regulated kinase, FAM20C, fibroblast growth factor receptor, hypophosphatemia, osteomalacia, rickets
INTRODUCTION Fibroblast growth factor 23 (FGF23) was cloned as a responsible gene for autosomal dominant hypophosphatemic rickets (ADHR) in 2000 [1]. Almost simultaneously, FGF23 was also identified as a responsible humoral factor for tumor-induced osteomalacia (TIO) [2]. Rickets and osteomalacia are diseases with impaired mineralization of bone matrix. Rickets develops in children before the closure of the growth plates. In contrast, osteomalacia is a disease of adulthood. ADHR and TIO are characterized by hypophosphatemia with impaired renal tubular reabsorption of phosphate. In addition, hypophosphatemia is known to simulate 1,25-dihydroxyvitamin D [1,25(OH)2D] production and increase circulatory 1,25(OH)2D level [3]. In contrast, 1,25(OH)2D is low to low-normal in patients with TIO and ADHR. Subsequent studies have shown that FGF23 is a bone-derived hormone and reduces proximal tubular phosphate reabsorption by suppressing the expression of type 2a and 2c sodiumphosphate cotransporters [4]. FGF23 was also shown to decrease 1,25(OH)2D levels by suppressing the www.co-nephrolhypertens.com
expression of Cyp27b1 encoding 25-hydroxyvitamin D [25(OH)D]-1a-hydroxylase, and also by enhancing Cyp24 expression for 25(OH)D-24-hydroxylase [4]. Therefore, biochemical features in patients with ADHR and TIO can be explained by the excess actions of FGF23. FGF23 requires Klotho in addition to a FGF receptor to accomplish these actions [5,6].
FIBROBLAST GROWTH FACTOR 23-RELATED HYPOPHOSPHATEMIC DISEASES X-linked hypophosphatemic rickets (XLHR) is the most frequent cause of vitamin D-resistant rickets Department of Medicine, Division of Nephrology and Endocrinology, University of Tokyo Hospital, Tokyo, Japan Correspondence to S. Fukumoto, MD, PhD, Department of Medicine, Division of Nephrology and Endocrinology, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81 3 3815 5411; fax: +81 3 5800 9836; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:346–351 DOI:10.1097/01.mnh.0000447012.98357.da Volume 23 Number 4 July 2014
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Anti-fibroblast growth factor 23 antibody therapy Fukumoto
KEY POINTS FGF23 works as a phosphotropic hormone, reducing serum phosphate and 1,25(OH)2D levels. Excess actions of FGF23 result in several kinds of hypophosphatemic rickets/osteomalacia. XLHR is the most frequent cause of hereditary FGF23related hypophosphatemic rickets. Several methods that inhibit FGF23 production or actions have been shown to increase serum phosphate in Hyp mice, model mice of XLHR. A clinical trial of humanized anti-FGF23 monoclonal antibody has started in adult patients with XLHR.
shown in Table 1 and Fig. 1 [13], and the spectrum of FGF23-related hypophosphatemic diseases is still expanding. Family with sequence similarity 20, member C (FAM20C) is a Golgi kinase that phosphorylates proteins in the Golgi apparatus [14]. Mutations in FAM20C were known to cause Raine syndrome, characterized by osteosclerosis [15]. Although Raine syndrome was originally considered to be lethal, some surviving patients were reported to have hypophosphatemia [16]. In addition, deletion of FAM20C in mice caused hypophosphatemic rickets and overexpression of FGF23 in bone [17]. Furthermore, exome sequence indicated that mutations in FAM20C can cause FGF23-related hypophosphatemia, dental anomalies and ectopic calcification [18 ]. In this case, the patient did not show rickets probably because of osteosclerotic features of Raine syndrome. Therefore, mutations in FAM20C seem to be able to induce somewhat contradictory phenotypes, osteosclerotic changes in Raine syndrome and FGF23-related hypophosphatemic disease. The precise mechanisms by which mutations in FAM20C cause osteosclerosis and overexpression of FGF23 remain to be clarified. However, FAM20C was shown to phosphorylate small integrin-binding ligand N-linked glycoproteins (SIBLINGs), including dentin matrix protein 1 (DMP1) [14]. Because mutations in DMP1 were shown to be responsible for autosomal recessive hypophosphatemic rickets 1 (ARHR1) [19,20], another FGF23-related hypophosphatemic rickets, it is possible that mutant FAM20C proteins induced FGF23 overexpression by modulating functions of DMP1. &&
and causes similar biochemical features to those of ADHR and TIO. Although the responsible gene for XLHR was cloned in 1995 and named phosphateregulating gene with homologies to endopeptidases on the X chromosome (PHEX) [7], it has been unclear how mutations in PHEX cause hypophosphatemic rickets. After the identification of FGF23, it was shown that patients with XLHR show a high circulatory level of FGF23 [8,9]. In addition, the Hyp mouse is a murine homologue of XLHR and has a deletion of the 3’-region of the PHEX gene. FGF23 was shown to be overexpressed in the bones of Hyp mice [10]. Furthermore, genetically engineered animals indicate that FGF23 is the causative factor for hypophosphatemia in Hyp mice [11,12]. Therefore, XLHR is also considered to be caused by excess actions of FGF23. More recently, FGF23 has been shown to cause hypophosphatemia in several diseases, as
Table 1. Hypophosphatemic diseases caused by excess actions of FGF23 Disease
Responsible gene
X-linked hypophosphatemic rickets: XLHR
PHEX
Autosomal dominant hypophosphatemic rickets: ADHR
FGF23
Autosomal recessive hypophosphatemic rickets 1: ARHR1
DMP1
Autosomal recessive hypophosphatemic rickets 2: ARHR2
ENPP1
McCune-Albright syndrome/fibrous dysplasia
GNAS1
Osteoglophonic dysplasia
FGFR1
Jansen-type metaphyseal chondrodysplasia
PTH1R
Hypophosphatemia, dental anomalies, ectopic calcification
FAM20C
Mosaic cutaneous and skeletal lesions, hypophosphatemia
HRAS, NRAS
Tumor-induced osteomalacia Hypophosphatemic disease by iron polymaltose or saccharated ferric oxide DMP1, dentin matrix protein 1; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; FAM20C, family with sequence similarity 20, member C; FGFR1, fibroblast growth factor receptor 1; GNAS1, guanine nucleotide binding protein, alpha stimulating; HRAS, Harvey rat sarcoma viral oncogene homologue; NRAS, neuroblastoma ras oncogene; PHEX, phosphate-regulating gene with homologies to endopeptidases on the X chromosome; PTH1R, parathyroid hormone 1 receptor.
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Mineral metabolism
FGFR1
FAM20C
HRAS, NRAS
GNAS PTH1R
? DMP1
ENPP1
ERK
cAMP ?
PHEX FGF23 production
?
Responsible tumor for TIO
FGF23 mutation
Iron polymaltose, saccharated ferric oxide
Excess FGF23 activity
?
FGF23-related hypophosphatemic diseases
FIGURE 1. Hypothetical model of the pathogenesis of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases. Overproduction of FGF23 and excess FGF23 activity causes FGF23-related hypophosphatemic diseases. Extracellular signal-regulated kinase (ERK) and cyclic AMP (cAMP) pathways were shown to regulate FGF23 production. PHEX, DMP1, ENPP1 and FAM20C are considered to suppress FGF23 production, whereas the precise functions of these proteins remain to be clarified. FGF23 mutations cause resistance of FGF23 protein for proteolytic cleavage and may result in enhanced FGF23 activity.
Hypophosphatemia with high FGF23 was reported in some patients with linear nevus sebaceous syndrome [21]. However, the exact source of FGF23 was not confirmed in these patients. Recently, two articles suggested that somatic mutations in HRAS or NRAS in bone cause high FGF23 levels in patients with both epidermal or melanocytic nevi and bone dysplasia [22 ,23 ]. Although it is not clear how mutations in HRAS or NRAS affect FGF23 level, the results again indicate that bone is regulating phosphate metabolism. TIO is a paraneoplastic syndrome usually caused by mesenchymal benign tumors. Most tumors responsible for TIO are pathologically classified as phosphaturic mesenchymal tumor, mixed connective tissue variant [24]. In addition to these mesenchymal tumors, colon and renal cell carcinomas were recently reported to cause TIO, while FGF23 levels were not reported in patients with renal cancers [25,26 ,27]. Therefore, epidermal malignancy also needs to be considered as a cause of TIO in suspected patients. &
&
&
TREATMENT OF FIBROBLAST GROWTH FACTOR 23-RELTAED HYPOPHOSPHATEMIC DISEASES TIO can be cured by complete resection of the responsible tumors. In addition, hypophosphatemia caused 348
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by intravenous administration of saccharated ferric oxide or iron polymaltose improves on discontinuing these drugs. However, most patients with FGF23related hypophosphatemic diseases, including those with TIO whose responsible tumors cannot be found or removed for some reason, are treated with phosphate and active vitamin D [28]. However, these medications can be associated with several adverse events such as gastrointestinal symptoms, secondary–tertiary hyperparathyroidism, hypercalcemia, hypercalciuria and nephrocalcinosis [28]. Now that it is evident that the excess actions of FGF23 are causing these diseases, the inhibition of the production or actions of FGF23 is theoretically ideal for these patients with FGF23-related hypophosphatemic diseases. Several methods have been shown to inhibit the production and actions of FGF23. A part of the FGF23 protein is proteolytically processed between 179 Arg and 180Ser before or during secretion from producing cells. FGF23 has FGF a homology region, as do other members of FGF family, in the N-terminal portion of this processing site, and the amino acid sequence in the C-terminal portion is unique for FGF23. Full-length FGF23 transduces signals by binding to a Klotho-FGF receptor complex. The C-terminal processed fragment of the FGF23 protein was shown to compete with full-length FGF23 for this binding to the Klotho-FGF receptor complex Volume 23 Number 4 July 2014
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Anti-fibroblast growth factor 23 antibody therapy Fukumoto
and inhibit the actions of FGF23 [29]. In addition, several reports indicate that signals through the FGF receptor enhance FGF23 production in bone. Therefore, it was shown that inhibitors of FGF receptor can suppress both the production and actions of FGF23 [30,31 ]. Furthermore, the inhibitor of extracellular signal-regulated kinase can prevent the phosphaturic actions of FGF23 [32,33]. All these measures were shown to increase serum phosphate of Hyp mice. Therefore, these measures are potentially useful for the treatment of FGF23-related hypophosphatemic diseases. However, inhibitors of FGF receptor and extracellular signal-regulated kinase may lack specificity for FGF23 actions because these molecules are involved in diverse cellular functions. No results using these methods have been reported in human patients with FGF23related hypophosphatemic diseases. &&
EFFECTS OF ANTI-FIBROBLAST GROWTH FACTOR 23 ANTIBODY IN WILD-TYPE MICE Several humanized monoclonal antibodies are currently used in patients with various diseases. The antireceptor activator of nuclear factor kB ligand (RANKL) antibody was recently introduced to treat cancer-induced bone disease and osteoporosis. The effects of these antibodies seem to be specific for the target molecules. In addition, several antibodies are used for chronic conditions. Therefore, it is possible that anti-FGF23 antibody is clinically useful for patients with FGF23-related hypophosphatemic diseases. Several kinds of anti-FGF23 antibodies have been created and some of these have been used for ELISA for FGF23 [8,9]. In addition, two kinds of monoclonal anti-FGF23 antibodies were shown to inhibit the actions of FGF23 both in vitro and in vivo [34]. FGF23 enhances Egr-1 promoter-driven luciferase reporter activity in cells expressing Klotho. FN1 and FC1 antibodies that recognize the Nterminal and C-terminal portion of the processing site of FGF23, respectively, inhibited this reporter activity by FGF23 in a dose-dependent manner. In addition, an in-vitro study suggested that FGF23 uses its N-terminal region for the association with FGF receptor, and its unique C-terminal portion for the binding to Klotho [34]. Furthermore, these antibodies increased serum phosphate and 1,25(OH)2D levels, enhanced the expression of type 2a sodiumphosphate cotransporter and Cyp27b1 and suppressed Cyp24 expression when injected into wildtype mice [34]. These changes are exactly the opposite of those induced by FGF23. Moreover, FGF23null mice and Klotho mice with severely reduced
expression of Klotho have been shown to have the similar phenotypes [35,36]. Therefore, these results confirmed that FGF23 is a physiological regulator of serum phosphate and 1,25(OH)2D levels. These studies also indicated that it is possible to inhibit the actions of FGF23 using these antibodies.
ANTI-FIBROBLAST GROWTH FACTOR 23 ANTIBODY FOR HYPOPHOSPHATEMIC DISEASES These antibodies were then tested in Hyp mice. These mice show hypophosphatemia with impaired renal tubular phosphate reabsorption and relatively low 1,25(OH)2D levels for hypophosphatemia. When FN1 and FC1 antibodies were injected into Hyp mice, these antibodies corrected hypophosphatemia and impaired renal tubular phosphate reabsorption, and increased 1,25(OH)2D levels [37]. Notably, serum phosphate levels in Hyp mice treated with a larger dose of the antibodies was higher than that of wild-type mice. As in wild-type mice, these antibodies increased the expression of type 2a sodium-phosphate cotransporter and Cyp27b1, and reduced that of Cyp24. Furthermore, a dosedependent increase in body weight and tail length was observed when these antibodies were repeatedly injected into growing mice once weekly starting at 4 weeks of age. These antibodies also improved the elongation of femoral and tibial bones and corrected enlarged epiphyses. Histologically, disorganized columnar structure of growth plates was alleviated by the antibodies and the growth plate thickness decreased in a dose-dependent manner. Furthermore, these antibodies improved the mineralization of osteoid, and a dose-dependent decrease of osteoid thickness was observed. Collectively, these results indicate that the inhibition of excess FGF23 activity by anti-FGF23 antibodies not only improved disordered mineral metabolism but also corrected bone mineralization and growth. Subsequent studies used Hyp mice of 16–18 weeks of age [38]. Although once weekly administration of anti-FGF23 antibodies did not increase femoral length at this age, serum phosphate and 1,25(OH)2D were increased by the treatment as in younger animals. This correction of hypophosphatemia and relatively low 1,25(OH)2D was associated with improved mineralization of bone. Furthermore, Hyp mice showed reduced grip power and spontaneous movement compared with those of wild-type mice. However, anti-FGF23 antibodies almost normalized this reduced grip strength, although they did not increase muscle weight adjusted by body weight, cross-sectional area of myofiber and number of myofibers. Anti-FGF23
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antibodies also increased spontaneous movement of Hyp mice in a dose-dependent manner. Muscle weakness and bone pain are major complaints of adult patients with osteomalacia, although the detailed mechanisms of these symptoms are not clear. The exact cause of reduced spontaneous movement of Hyp mice is not known either. However, it is speculated that Hyp mice showed reduced spontaneous movement at least in part by muscle weakness or bone pain because these mice show clear hypophosphatemia and reduced muscle power. Therefore, studies using Hyp mice suggested that the inhibition of FGF23 activity by anti-FGF23 antibodies ameliorates biochemical, morphological, histological and clinical abnormalities of FGF23related hypophosphatemic diseases. Based on these animal studies, a phase I clinical trial of humanized anti-FGF23 monoclonal antibody for adult patients with XLHR has begun in North America. A recent report from this trial indicated that the anti-FGF23 antibody also increased serum phosphate and 1,25(OH)2D in human patients with XLHR [39 ]. It is possible that this anti-FGF23 antibody is useful for other FGF23related hypophosphatemic diseases than XLHR. It is sometimes very difficult to find the responsible tumors for TIO. In addition, even when the tumors are found, in some cases it is impossible to completely remove them because of the location of tumors or co-existing diseases. Anti-FGF23 antibody might be useful for these patients with TIO. However, several questions need to be answered before the clinical use of anti-FGF23 antibody. First, it has not been established in human whether the antibody improves growth and prevents the development of bone deformities in child patients with FGF23-related hypophosphatemic rickets. Second, it is not known either whether the inhibition of FGF23 activity ameliorates the symptoms of adult patients with FGF23-related hypophosphatemic osteomalacia. Third, long-term safety clearly needs to be evaluated in more studies. Even with these limitations, the anti-FGF23 antibody seems to be promising as a new therapeutic measure for hypophosphatemic diseases caused by excess actions of FGF23. &&
CONCLUSION The identification of FGF23 made it possible to interpret some kinds of rickets and osteomalacia as endocrine diseases. Diseases with excess hormone actions are now treated by drugs that inhibit the production or actions of the hormone. Therefore, although further studies are clearly necessary, it is possible that patients will be better managed by 350
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these new methods which inhibit the production or actions of FGF23. Acknowledgements None. Conflicts of interest S.F. received a consulting fee from Kyowa Hakko Kirin Co., Ltd.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26:345–348. 2. 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. 3. Hughes MR, Brumbaugh PF, Hussler MR, et al. Regulation of serum 1alpha,25-dihydroxyvitamin D3 by calcium and phosphate in the rat. Science 1975; 190:578–580. 4. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19:429–435. 5. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor23 signaling by klotho. J Biol Chem 2006; 281:6120–6123. 6. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770–774. 7. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 1995; 11:130–136. 8. 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. 9. 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. 10. Liu S, Guo R, Simpson LG, et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 2003; 278:37419– 37426. 11. Sitara D, Razzaque MS, Hesse M, et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 2004; 23:421–432. 12. Yuan B, Takaiwa M, Clemens TL, et al. Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest 2008; 118:722–734. 13. Fukumoto S, Shimizu Y. Fibroblast growth factor 23 as a phosphotropic hormone and beyond. J Bone Miner Metab 2011; 29:507–514. 14. Tagliabracci VS, Engel JL, Wen J, et al. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science 2012; 336:1150–1153. 15. Simpson MA, Hsu R, Keir LS, et al. Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet 2007; 81:906–912. 16. Simpson MA, Scheuerle A, Hurst J, et al. Mutations in FAM20C also identified in nonlethal osteosclerotic bone dysplasia. Clin Genet 2009; 75:271–276. 17. Wang X, Wang S, Li C, et al. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet 2012; 8:e1002708. 18. Rafaelsen SH, Raeder H, Fagerheim AK, et al. Exome sequencing reveals && FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res 2013; 28:1378–1385. This is the first study to report that mutations in FAM20C can cause FGF23-related hypophosphatemic disease in human. 19. Feng JQ, Ward LM, Liu S, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006; 38:1310–1315. 20. Lorenz-Depiereux B, Bastepe M, Benet-Pages A, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 2006; 38:1248–1250.
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Anti-fibroblast growth factor 23 antibody therapy Fukumoto 21. Hoffman WH, Jueppner HW, Deyoung BR, et al. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A 2005; 134:233–236. 22. Avitan-Hersh E, Tatur S, Indelman M, et al. Postzygotic HRAS mutation & causing both keratinocytic epidermal nevus and thymoma and associated with bone dysplasia and hypophosphatemia due to elevated FGF23. J Clin Endocrinol Metab 2014; 99:E132–E136. This article indicates that a somatic mutation in HRAS may be the cause of FGF23related hypophosphatemic disease. 23. Lim YH, Ovejero D, Sugarman JS, et al. Multilineage somatic activating & mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum Mol Genet 2014; 23:397– 407. This article also suggests that somatic mutations in HRAS and NRAS are the cause of FGF23-related hypophosphatemia. 24. Folpe AL, Fanburg-Smith JC, Billings SD, et al. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol 2004; 28:1–30. 25. Jin X, Jing H, Li F, Zhuang H. Osteomalacia-inducing renal clear cell carcinoma uncovered by 99mTc-Hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNICTOC) scintigraphy. Clin Nucl Med 2013; 38:922–924. 26. Leaf DE, Pereira RC, Bazari H, Juppner H. Oncogenic osteomalacia due to & FGF23-expressing colon adenocarcinoma. J Clin Endocrinol Metab 2013; 98:887–891. This article clearly indicates that epidermal cancer can cause tumor-induced osteomalacia by overexpressing FGF23. 27. Xie Y, Li HZ. Oncogenic osteomalacia caused by renal cell carcinoma. J Clin Endocrinol Metab 2013; 98:4597–4598. 28. Carpenter TO, Imel EA, Holm IA, et al. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res 2011; 26:1381–1388. 29. Goetz R, Nakada Y, Hu MC, et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A 2010; 107:407–412.
30. Wohrle S, Bonny O, Beluch N, et al. FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res 2011; 26:2486–2497. 31. Wohrle S, Henninger C, Bonny O, et al. Pharmacological inhibition of && fibroblast growth factor (FGF) receptor signaling ameliorates FGF23mediated hypophosphatemic rickets. J Bone Miner Res 2013; 28:899–911. This article indicates that NVP-BGJ398, a pan-specific FGFR inhibitor, increased serum phosphate in both Hyp and DMP1-null mice by inhibiting signaling induced by FGF23. 32. Ranch D, Zhang MY, Portale AA, Perwad F. Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice. J Bone Miner Res 2011; 26:1883–1890. 33. Zhang MY, Ranch D, Pereira RC, et al. Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice. Endocrinology 2012; 153:1806–1816. 34. Yamazaki Y, Tamada T, Kasai N, et al. Anti-FGF23 neutralizing antibodies demonstrate the physiological role and structural features of FGF23. J Bone Miner Res 2008; 23:1509–1518. 35. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390:45–51. 36. Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF-23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113:561–568. 37. Aono Y, Yamazaki Y, Yasutake J, et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res 2009; 24:1879–1888. 38. Aono Y, Hasegawa H, Yamazaki Y, et al. Anti-FGF23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. J Bone Miner Res 2011; 26:803–810. 39. Carpenter TO, Imel E, Ruppe M, et al. Randomized trial of the anti-FGF23 anti&& body KRN23 in X-linked hypophosphatemia. J Clin Invest 2014; 124:1587– 1597. This article indicates that the inhibition of FGF23 activity by a monoclonal antiFGF23 antibody increases serum phosphate and 1,25(OH)2D in human patients with XLHR for the first time.
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Anti-fibroblast growth factor 23 antibody therapy Seiji Fukumoto
Purpose of review The review is intended to provide an update on the expanding knowledge regarding diseases caused by the excess actions of fibroblast growth factor 23 (FGF23) and also on the new therapeutic measures for these diseases, with an emphasis on the anti-FGF23 antibody. Recent findings FGF23 decreases serum phosphate and 1,25-dihydroxyvitamin D levels. After the cloning of FGF23, several hypophosphatemic diseases, including tumor-induced osteomalacia and X-linked hypophosphatemic rickets (XLHR), were shown to be caused by excess actions of FGF23. In addition, recent studies indicated that mutations in the family with sequence similarity 20, member C (FAM20C), HRAS and NRAS genes, also caused FGF23-related hypophosphatemic diseases. The inhibition of FGF23 production or activity is, theoretically, an ideal treatment for these hypophosphatemic diseases. The C-terminal fragment of FGF23, inhibitors of FGF receptor and extracellular signal-regulated kinase, and anti-FGF23 antibody were shown to inhibit FGF23 actions both in vitro and in vivo. A phase I clinical trial of anti-FGF23 antibody has shown that this antibody increases serum phosphate in patients with XLHR. Summary These recent findings confirm that FGF23 has a pivotal role in phosphate metabolism. The inhibition of FGF23 production or activity is promising as a new therapy for FGF23-related hypophosphatemic diseases. Further studies are clearly necessary to establish the clinical utility and long-term safety of these measures. Keywords extracellular signal-regulated kinase, FAM20C, fibroblast growth factor receptor, hypophosphatemia, osteomalacia, rickets
INTRODUCTION Fibroblast growth factor 23 (FGF23) was cloned as a responsible gene for autosomal dominant hypophosphatemic rickets (ADHR) in 2000 [1]. Almost simultaneously, FGF23 was also identified as a responsible humoral factor for tumor-induced osteomalacia (TIO) [2]. Rickets and osteomalacia are diseases with impaired mineralization of bone matrix. Rickets develops in children before the closure of the growth plates. In contrast, osteomalacia is a disease of adulthood. ADHR and TIO are characterized by hypophosphatemia with impaired renal tubular reabsorption of phosphate. In addition, hypophosphatemia is known to simulate 1,25-dihydroxyvitamin D [1,25(OH)2D] production and increase circulatory 1,25(OH)2D level [3]. In contrast, 1,25(OH)2D is low to low-normal in patients with TIO and ADHR. Subsequent studies have shown that FGF23 is a bone-derived hormone and reduces proximal tubular phosphate reabsorption by suppressing the expression of type 2a and 2c sodiumphosphate cotransporters [4]. FGF23 was also shown to decrease 1,25(OH)2D levels by suppressing the www.co-nephrolhypertens.com
expression of Cyp27b1 encoding 25-hydroxyvitamin D [25(OH)D]-1a-hydroxylase, and also by enhancing Cyp24 expression for 25(OH)D-24-hydroxylase [4]. Therefore, biochemical features in patients with ADHR and TIO can be explained by the excess actions of FGF23. FGF23 requires Klotho in addition to a FGF receptor to accomplish these actions [5,6].
FIBROBLAST GROWTH FACTOR 23-RELATED HYPOPHOSPHATEMIC DISEASES X-linked hypophosphatemic rickets (XLHR) is the most frequent cause of vitamin D-resistant rickets Department of Medicine, Division of Nephrology and Endocrinology, University of Tokyo Hospital, Tokyo, Japan Correspondence to S. Fukumoto, MD, PhD, Department of Medicine, Division of Nephrology and Endocrinology, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81 3 3815 5411; fax: +81 3 5800 9836; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:346–351 DOI:10.1097/01.mnh.0000447012.98357.da Volume 23 Number 4 July 2014
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Anti-fibroblast growth factor 23 antibody therapy Fukumoto
KEY POINTS FGF23 works as a phosphotropic hormone, reducing serum phosphate and 1,25(OH)2D levels. Excess actions of FGF23 result in several kinds of hypophosphatemic rickets/osteomalacia. XLHR is the most frequent cause of hereditary FGF23related hypophosphatemic rickets. Several methods that inhibit FGF23 production or actions have been shown to increase serum phosphate in Hyp mice, model mice of XLHR. A clinical trial of humanized anti-FGF23 monoclonal antibody has started in adult patients with XLHR.
shown in Table 1 and Fig. 1 [13], and the spectrum of FGF23-related hypophosphatemic diseases is still expanding. Family with sequence similarity 20, member C (FAM20C) is a Golgi kinase that phosphorylates proteins in the Golgi apparatus [14]. Mutations in FAM20C were known to cause Raine syndrome, characterized by osteosclerosis [15]. Although Raine syndrome was originally considered to be lethal, some surviving patients were reported to have hypophosphatemia [16]. In addition, deletion of FAM20C in mice caused hypophosphatemic rickets and overexpression of FGF23 in bone [17]. Furthermore, exome sequence indicated that mutations in FAM20C can cause FGF23-related hypophosphatemia, dental anomalies and ectopic calcification [18 ]. In this case, the patient did not show rickets probably because of osteosclerotic features of Raine syndrome. Therefore, mutations in FAM20C seem to be able to induce somewhat contradictory phenotypes, osteosclerotic changes in Raine syndrome and FGF23-related hypophosphatemic disease. The precise mechanisms by which mutations in FAM20C cause osteosclerosis and overexpression of FGF23 remain to be clarified. However, FAM20C was shown to phosphorylate small integrin-binding ligand N-linked glycoproteins (SIBLINGs), including dentin matrix protein 1 (DMP1) [14]. Because mutations in DMP1 were shown to be responsible for autosomal recessive hypophosphatemic rickets 1 (ARHR1) [19,20], another FGF23-related hypophosphatemic rickets, it is possible that mutant FAM20C proteins induced FGF23 overexpression by modulating functions of DMP1. &&
and causes similar biochemical features to those of ADHR and TIO. Although the responsible gene for XLHR was cloned in 1995 and named phosphateregulating gene with homologies to endopeptidases on the X chromosome (PHEX) [7], it has been unclear how mutations in PHEX cause hypophosphatemic rickets. After the identification of FGF23, it was shown that patients with XLHR show a high circulatory level of FGF23 [8,9]. In addition, the Hyp mouse is a murine homologue of XLHR and has a deletion of the 3’-region of the PHEX gene. FGF23 was shown to be overexpressed in the bones of Hyp mice [10]. Furthermore, genetically engineered animals indicate that FGF23 is the causative factor for hypophosphatemia in Hyp mice [11,12]. Therefore, XLHR is also considered to be caused by excess actions of FGF23. More recently, FGF23 has been shown to cause hypophosphatemia in several diseases, as
Table 1. Hypophosphatemic diseases caused by excess actions of FGF23 Disease
Responsible gene
X-linked hypophosphatemic rickets: XLHR
PHEX
Autosomal dominant hypophosphatemic rickets: ADHR
FGF23
Autosomal recessive hypophosphatemic rickets 1: ARHR1
DMP1
Autosomal recessive hypophosphatemic rickets 2: ARHR2
ENPP1
McCune-Albright syndrome/fibrous dysplasia
GNAS1
Osteoglophonic dysplasia
FGFR1
Jansen-type metaphyseal chondrodysplasia
PTH1R
Hypophosphatemia, dental anomalies, ectopic calcification
FAM20C
Mosaic cutaneous and skeletal lesions, hypophosphatemia
HRAS, NRAS
Tumor-induced osteomalacia Hypophosphatemic disease by iron polymaltose or saccharated ferric oxide DMP1, dentin matrix protein 1; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; FAM20C, family with sequence similarity 20, member C; FGFR1, fibroblast growth factor receptor 1; GNAS1, guanine nucleotide binding protein, alpha stimulating; HRAS, Harvey rat sarcoma viral oncogene homologue; NRAS, neuroblastoma ras oncogene; PHEX, phosphate-regulating gene with homologies to endopeptidases on the X chromosome; PTH1R, parathyroid hormone 1 receptor.
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Mineral metabolism
FGFR1
FAM20C
HRAS, NRAS
GNAS PTH1R
? DMP1
ENPP1
ERK
cAMP ?
PHEX FGF23 production
?
Responsible tumor for TIO
FGF23 mutation
Iron polymaltose, saccharated ferric oxide
Excess FGF23 activity
?
FGF23-related hypophosphatemic diseases
FIGURE 1. Hypothetical model of the pathogenesis of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases. Overproduction of FGF23 and excess FGF23 activity causes FGF23-related hypophosphatemic diseases. Extracellular signal-regulated kinase (ERK) and cyclic AMP (cAMP) pathways were shown to regulate FGF23 production. PHEX, DMP1, ENPP1 and FAM20C are considered to suppress FGF23 production, whereas the precise functions of these proteins remain to be clarified. FGF23 mutations cause resistance of FGF23 protein for proteolytic cleavage and may result in enhanced FGF23 activity.
Hypophosphatemia with high FGF23 was reported in some patients with linear nevus sebaceous syndrome [21]. However, the exact source of FGF23 was not confirmed in these patients. Recently, two articles suggested that somatic mutations in HRAS or NRAS in bone cause high FGF23 levels in patients with both epidermal or melanocytic nevi and bone dysplasia [22 ,23 ]. Although it is not clear how mutations in HRAS or NRAS affect FGF23 level, the results again indicate that bone is regulating phosphate metabolism. TIO is a paraneoplastic syndrome usually caused by mesenchymal benign tumors. Most tumors responsible for TIO are pathologically classified as phosphaturic mesenchymal tumor, mixed connective tissue variant [24]. In addition to these mesenchymal tumors, colon and renal cell carcinomas were recently reported to cause TIO, while FGF23 levels were not reported in patients with renal cancers [25,26 ,27]. Therefore, epidermal malignancy also needs to be considered as a cause of TIO in suspected patients. &
&
&
TREATMENT OF FIBROBLAST GROWTH FACTOR 23-RELTAED HYPOPHOSPHATEMIC DISEASES TIO can be cured by complete resection of the responsible tumors. In addition, hypophosphatemia caused 348
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by intravenous administration of saccharated ferric oxide or iron polymaltose improves on discontinuing these drugs. However, most patients with FGF23related hypophosphatemic diseases, including those with TIO whose responsible tumors cannot be found or removed for some reason, are treated with phosphate and active vitamin D [28]. However, these medications can be associated with several adverse events such as gastrointestinal symptoms, secondary–tertiary hyperparathyroidism, hypercalcemia, hypercalciuria and nephrocalcinosis [28]. Now that it is evident that the excess actions of FGF23 are causing these diseases, the inhibition of the production or actions of FGF23 is theoretically ideal for these patients with FGF23-related hypophosphatemic diseases. Several methods have been shown to inhibit the production and actions of FGF23. A part of the FGF23 protein is proteolytically processed between 179 Arg and 180Ser before or during secretion from producing cells. FGF23 has FGF a homology region, as do other members of FGF family, in the N-terminal portion of this processing site, and the amino acid sequence in the C-terminal portion is unique for FGF23. Full-length FGF23 transduces signals by binding to a Klotho-FGF receptor complex. The C-terminal processed fragment of the FGF23 protein was shown to compete with full-length FGF23 for this binding to the Klotho-FGF receptor complex Volume 23 Number 4 July 2014
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Anti-fibroblast growth factor 23 antibody therapy Fukumoto
and inhibit the actions of FGF23 [29]. In addition, several reports indicate that signals through the FGF receptor enhance FGF23 production in bone. Therefore, it was shown that inhibitors of FGF receptor can suppress both the production and actions of FGF23 [30,31 ]. Furthermore, the inhibitor of extracellular signal-regulated kinase can prevent the phosphaturic actions of FGF23 [32,33]. All these measures were shown to increase serum phosphate of Hyp mice. Therefore, these measures are potentially useful for the treatment of FGF23-related hypophosphatemic diseases. However, inhibitors of FGF receptor and extracellular signal-regulated kinase may lack specificity for FGF23 actions because these molecules are involved in diverse cellular functions. No results using these methods have been reported in human patients with FGF23related hypophosphatemic diseases. &&
EFFECTS OF ANTI-FIBROBLAST GROWTH FACTOR 23 ANTIBODY IN WILD-TYPE MICE Several humanized monoclonal antibodies are currently used in patients with various diseases. The antireceptor activator of nuclear factor kB ligand (RANKL) antibody was recently introduced to treat cancer-induced bone disease and osteoporosis. The effects of these antibodies seem to be specific for the target molecules. In addition, several antibodies are used for chronic conditions. Therefore, it is possible that anti-FGF23 antibody is clinically useful for patients with FGF23-related hypophosphatemic diseases. Several kinds of anti-FGF23 antibodies have been created and some of these have been used for ELISA for FGF23 [8,9]. In addition, two kinds of monoclonal anti-FGF23 antibodies were shown to inhibit the actions of FGF23 both in vitro and in vivo [34]. FGF23 enhances Egr-1 promoter-driven luciferase reporter activity in cells expressing Klotho. FN1 and FC1 antibodies that recognize the Nterminal and C-terminal portion of the processing site of FGF23, respectively, inhibited this reporter activity by FGF23 in a dose-dependent manner. In addition, an in-vitro study suggested that FGF23 uses its N-terminal region for the association with FGF receptor, and its unique C-terminal portion for the binding to Klotho [34]. Furthermore, these antibodies increased serum phosphate and 1,25(OH)2D levels, enhanced the expression of type 2a sodiumphosphate cotransporter and Cyp27b1 and suppressed Cyp24 expression when injected into wildtype mice [34]. These changes are exactly the opposite of those induced by FGF23. Moreover, FGF23null mice and Klotho mice with severely reduced
expression of Klotho have been shown to have the similar phenotypes [35,36]. Therefore, these results confirmed that FGF23 is a physiological regulator of serum phosphate and 1,25(OH)2D levels. These studies also indicated that it is possible to inhibit the actions of FGF23 using these antibodies.
ANTI-FIBROBLAST GROWTH FACTOR 23 ANTIBODY FOR HYPOPHOSPHATEMIC DISEASES These antibodies were then tested in Hyp mice. These mice show hypophosphatemia with impaired renal tubular phosphate reabsorption and relatively low 1,25(OH)2D levels for hypophosphatemia. When FN1 and FC1 antibodies were injected into Hyp mice, these antibodies corrected hypophosphatemia and impaired renal tubular phosphate reabsorption, and increased 1,25(OH)2D levels [37]. Notably, serum phosphate levels in Hyp mice treated with a larger dose of the antibodies was higher than that of wild-type mice. As in wild-type mice, these antibodies increased the expression of type 2a sodium-phosphate cotransporter and Cyp27b1, and reduced that of Cyp24. Furthermore, a dosedependent increase in body weight and tail length was observed when these antibodies were repeatedly injected into growing mice once weekly starting at 4 weeks of age. These antibodies also improved the elongation of femoral and tibial bones and corrected enlarged epiphyses. Histologically, disorganized columnar structure of growth plates was alleviated by the antibodies and the growth plate thickness decreased in a dose-dependent manner. Furthermore, these antibodies improved the mineralization of osteoid, and a dose-dependent decrease of osteoid thickness was observed. Collectively, these results indicate that the inhibition of excess FGF23 activity by anti-FGF23 antibodies not only improved disordered mineral metabolism but also corrected bone mineralization and growth. Subsequent studies used Hyp mice of 16–18 weeks of age [38]. Although once weekly administration of anti-FGF23 antibodies did not increase femoral length at this age, serum phosphate and 1,25(OH)2D were increased by the treatment as in younger animals. This correction of hypophosphatemia and relatively low 1,25(OH)2D was associated with improved mineralization of bone. Furthermore, Hyp mice showed reduced grip power and spontaneous movement compared with those of wild-type mice. However, anti-FGF23 antibodies almost normalized this reduced grip strength, although they did not increase muscle weight adjusted by body weight, cross-sectional area of myofiber and number of myofibers. Anti-FGF23
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antibodies also increased spontaneous movement of Hyp mice in a dose-dependent manner. Muscle weakness and bone pain are major complaints of adult patients with osteomalacia, although the detailed mechanisms of these symptoms are not clear. The exact cause of reduced spontaneous movement of Hyp mice is not known either. However, it is speculated that Hyp mice showed reduced spontaneous movement at least in part by muscle weakness or bone pain because these mice show clear hypophosphatemia and reduced muscle power. Therefore, studies using Hyp mice suggested that the inhibition of FGF23 activity by anti-FGF23 antibodies ameliorates biochemical, morphological, histological and clinical abnormalities of FGF23related hypophosphatemic diseases. Based on these animal studies, a phase I clinical trial of humanized anti-FGF23 monoclonal antibody for adult patients with XLHR has begun in North America. A recent report from this trial indicated that the anti-FGF23 antibody also increased serum phosphate and 1,25(OH)2D in human patients with XLHR [39 ]. It is possible that this anti-FGF23 antibody is useful for other FGF23related hypophosphatemic diseases than XLHR. It is sometimes very difficult to find the responsible tumors for TIO. In addition, even when the tumors are found, in some cases it is impossible to completely remove them because of the location of tumors or co-existing diseases. Anti-FGF23 antibody might be useful for these patients with TIO. However, several questions need to be answered before the clinical use of anti-FGF23 antibody. First, it has not been established in human whether the antibody improves growth and prevents the development of bone deformities in child patients with FGF23-related hypophosphatemic rickets. Second, it is not known either whether the inhibition of FGF23 activity ameliorates the symptoms of adult patients with FGF23-related hypophosphatemic osteomalacia. Third, long-term safety clearly needs to be evaluated in more studies. Even with these limitations, the anti-FGF23 antibody seems to be promising as a new therapeutic measure for hypophosphatemic diseases caused by excess actions of FGF23. &&
CONCLUSION The identification of FGF23 made it possible to interpret some kinds of rickets and osteomalacia as endocrine diseases. Diseases with excess hormone actions are now treated by drugs that inhibit the production or actions of the hormone. Therefore, although further studies are clearly necessary, it is possible that patients will be better managed by 350
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these new methods which inhibit the production or actions of FGF23. Acknowledgements None. Conflicts of interest S.F. received a consulting fee from Kyowa Hakko Kirin Co., Ltd.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26:345–348. 2. 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. 3. Hughes MR, Brumbaugh PF, Hussler MR, et al. Regulation of serum 1alpha,25-dihydroxyvitamin D3 by calcium and phosphate in the rat. Science 1975; 190:578–580. 4. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19:429–435. 5. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor23 signaling by klotho. J Biol Chem 2006; 281:6120–6123. 6. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770–774. 7. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 1995; 11:130–136. 8. 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. 9. 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. 10. Liu S, Guo R, Simpson LG, et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 2003; 278:37419– 37426. 11. Sitara D, Razzaque MS, Hesse M, et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 2004; 23:421–432. 12. Yuan B, Takaiwa M, Clemens TL, et al. Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest 2008; 118:722–734. 13. Fukumoto S, Shimizu Y. Fibroblast growth factor 23 as a phosphotropic hormone and beyond. J Bone Miner Metab 2011; 29:507–514. 14. Tagliabracci VS, Engel JL, Wen J, et al. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science 2012; 336:1150–1153. 15. Simpson MA, Hsu R, Keir LS, et al. Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet 2007; 81:906–912. 16. Simpson MA, Scheuerle A, Hurst J, et al. Mutations in FAM20C also identified in nonlethal osteosclerotic bone dysplasia. Clin Genet 2009; 75:271–276. 17. Wang X, Wang S, Li C, et al. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet 2012; 8:e1002708. 18. Rafaelsen SH, Raeder H, Fagerheim AK, et al. Exome sequencing reveals && FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res 2013; 28:1378–1385. This is the first study to report that mutations in FAM20C can cause FGF23-related hypophosphatemic disease in human. 19. Feng JQ, Ward LM, Liu S, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006; 38:1310–1315. 20. Lorenz-Depiereux B, Bastepe M, Benet-Pages A, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 2006; 38:1248–1250.
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Anti-fibroblast growth factor 23 antibody therapy Fukumoto 21. Hoffman WH, Jueppner HW, Deyoung BR, et al. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A 2005; 134:233–236. 22. Avitan-Hersh E, Tatur S, Indelman M, et al. Postzygotic HRAS mutation & causing both keratinocytic epidermal nevus and thymoma and associated with bone dysplasia and hypophosphatemia due to elevated FGF23. J Clin Endocrinol Metab 2014; 99:E132–E136. This article indicates that a somatic mutation in HRAS may be the cause of FGF23related hypophosphatemic disease. 23. Lim YH, Ovejero D, Sugarman JS, et al. Multilineage somatic activating & mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum Mol Genet 2014; 23:397– 407. This article also suggests that somatic mutations in HRAS and NRAS are the cause of FGF23-related hypophosphatemia. 24. Folpe AL, Fanburg-Smith JC, Billings SD, et al. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol 2004; 28:1–30. 25. Jin X, Jing H, Li F, Zhuang H. Osteomalacia-inducing renal clear cell carcinoma uncovered by 99mTc-Hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNICTOC) scintigraphy. Clin Nucl Med 2013; 38:922–924. 26. Leaf DE, Pereira RC, Bazari H, Juppner H. Oncogenic osteomalacia due to & FGF23-expressing colon adenocarcinoma. J Clin Endocrinol Metab 2013; 98:887–891. This article clearly indicates that epidermal cancer can cause tumor-induced osteomalacia by overexpressing FGF23. 27. Xie Y, Li HZ. Oncogenic osteomalacia caused by renal cell carcinoma. J Clin Endocrinol Metab 2013; 98:4597–4598. 28. Carpenter TO, Imel EA, Holm IA, et al. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res 2011; 26:1381–1388. 29. Goetz R, Nakada Y, Hu MC, et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A 2010; 107:407–412.
30. Wohrle S, Bonny O, Beluch N, et al. FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res 2011; 26:2486–2497. 31. Wohrle S, Henninger C, Bonny O, et al. Pharmacological inhibition of && fibroblast growth factor (FGF) receptor signaling ameliorates FGF23mediated hypophosphatemic rickets. J Bone Miner Res 2013; 28:899–911. This article indicates that NVP-BGJ398, a pan-specific FGFR inhibitor, increased serum phosphate in both Hyp and DMP1-null mice by inhibiting signaling induced by FGF23. 32. Ranch D, Zhang MY, Portale AA, Perwad F. Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice. J Bone Miner Res 2011; 26:1883–1890. 33. Zhang MY, Ranch D, Pereira RC, et al. Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice. Endocrinology 2012; 153:1806–1816. 34. Yamazaki Y, Tamada T, Kasai N, et al. Anti-FGF23 neutralizing antibodies demonstrate the physiological role and structural features of FGF23. J Bone Miner Res 2008; 23:1509–1518. 35. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390:45–51. 36. Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF-23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113:561–568. 37. Aono Y, Yamazaki Y, Yasutake J, et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res 2009; 24:1879–1888. 38. Aono Y, Hasegawa H, Yamazaki Y, et al. Anti-FGF23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. J Bone Miner Res 2011; 26:803–810. 39. Carpenter TO, Imel E, Ruppe M, et al. Randomized trial of the anti-FGF23 anti&& body KRN23 in X-linked hypophosphatemia. J Clin Invest 2014; 124:1587– 1597. This article indicates that the inhibition of FGF23 activity by a monoclonal antiFGF23 antibody increases serum phosphate and 1,25(OH)2D in human patients with XLHR for the first time.
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