Endocrine Journal 2008, 55 (1), 23–31 REVIEW Actions and Mode of Actions of FGF19 Subfamily Members SEIJI FUKUMOTO Division of Nephrology & Endocrinology, Department of Medicine, University of Tokyo Hospital, Tokyo 113-8655, Japan Abstract. Fibroblast growth factors (FGFs) are humoral factors with diverse biological functions. While most FGFs were shown to work as local factors regulating cell growth and differentiation, recent investigations indicated that FGF19 subfamily members, FGF15/19, FGF21 and FGF23 work as systemic factors. FGF15/19 produced by intestine inhibits bile acid synthesis and FGF21from liver is involved in carbohydrate and lipid metabolism. In addition, FGF23 was shown to be produced by bone and regulate phosphate and vitamin D metabolism. Furthermore, these FGFs require klotho or βklotho for their actions in addition to canonical FGF receptors. It is possible that these FGFs together with their receptor systems might be targets for novel therapeutic measures in the future. Key words: Hypophosphatemia, Hyperphosphatemia, Klotho, FGF (Endocrine Journal 55: 23–31, 2008) FIBROBLAST growth factors (FGFs) are humoral FGF23 factors with diverse biological functions. It has been proposed that there are 22 members of FGF family in Identification and action of FGF23 human (FGF1 to FGF14, and FGF16 to FGF23) and these family members are divided into several subfam- FGF23 is the latest member of FGF family. We ilies [1] (Table 1). However, 4 members, FGF11 to have reviewed FGF23 as a responsible factor for hypo- FGF14, have been shown to be unable to bind to and phosphatemic rickets/osteomalacia in 2001 [4]. Since activate FGF receptors (FGFRs) [2]. These factors are then, significant progress has been made in the under- also called as FGF homologous factors and discrimi- standing of physiological and pathophysiological im- nated from other members of FGF family by some re- portance of FGF23. FGF23 was identified almost searchers [3]. Most FGFs have been shown to work as simultaneously by three groups by different approaches. local factors regulating cell growth and differentiation. FGF23 was first cloned by homology to FGF15, a mu- In contrast, recent findings concerning actions and rine orthologue of human FGF19, in mice [5]. The mode of actions of FGF19 subfamily members clearly same group cloned human FGF23 as well. FGF23 expanded our knowledge about the biological signifi- was also cloned as a responsible gene for autosomal cance of FGF family members. In this review, charac- dominant hypophosphatemic rickets/osteomalacia teristics of FGF19 subfamily members are summarized (ADHR) by positional cloning [6] and as a causative with special emphasis on FGF23. humoral factor for tumor-induced rickets/osteomalacia (TIO) [7]. Rickets/osteomalacia is characterized by impaired mineralization of bone matrix. There are many causes for rickets/osteomalacia as shown in Ta- ble 2. Of these, several hypophosphatemic diseases Received: August 4, 2007 are known to share common clinical features. Those Accepted: August 5, 2007 Correspondence to: Dr. Seiji FUKUMOTO, Division of Neph- include ADHR, autosomal recessive hypophosphatemic rology & Endocrinology, Department of Medicine, University of rickets/osteomalacia (ARHR), X-linked hypophos- Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, phatemic rickets/osteomalacia (XLH), TIO and hypo- Japan phosphatemic rickets/osteomalacia associated with 24 FUKUMOTO Table 1. FGF family members Table 2. Causes of rickets/osteomalacia Causative genes were described in brackets. Diseases FGF1 subfamily caused by excess actions of FGF23 are underlined. FGF1 (Acidic FGF) Although McCune-Albright syndrome is not a herita- FGF2 (Basic FGF) ble disease, its genetic cause has been clarified. FGF4 subfamily FGF4 Genetic causes FGF5 X-linked hypophosphatemic rickets/osteomalacia (XLH) FGF6 [PHEX] FGF7 subfamily Autosomal recessive hypophosphatemic rickets/osteomalacia FGF3 (ARHR) [DMP1] FGF7 Autosomal dominant hypophosphatemic rickets/osteomalacia FGF10 (ADHR) [FGF23] FGF22 Hereditary hypophosphatemic rickets/osteomalacia with FGF8 subfamily hypercalciuria (HHRH) [SLC34A3] FGF8 FGF17 Vitamin D dependency type I [CYP27B1] FGF18 Vitamin D dependency type II [VDR] FGF9 subfamily Selective 25-hydroxyvitamin D deficiency [CYP2R1] FGF9 Hypophosphatasia [Alkaline phosphatase] FGF16 FGF20 Renal tubular diseases (Dent's disease [CLC5], distal renal FGF11 subfamily tubular acidosis [SLC4A1] ...) FGF11 (FHF*3) McCune-Albright syndrome/Fibrous dysplasia [GNAS] FGF12 (FHF1) Acquired causes FGF13 (FHF2) Vitamin D deficiency FGF14 (FHF4) Malabsorption (malnutrition, gastrointestinal diseases ...) FGF19 subfamily FGF19 Chronic renal failure FGF21 Drugs (anticonvulsant, aluminum ...) FGF23 Tumor-induced rickets/osteomalacia (TIO) * FHF: FGF homologous factor Renal tubular diseases PHEX: phosphate-regulating gene with homologies to endopeptidases on the X chromosome DMP1: dentin matrix protein 1 McCune-Albright syndrome (MAS)/fibrous dysplasia VDR: vitamin D receptor (FD). These diseases are characterized by rickets/os- CLC: chloride channel teomalacia and hypophosphatemia at least in part due to GNAS: guanine nucleotide-binding protein G-stimulatory impaired proximal tubular phosphate reabsorption. subunit alpha Hypophosphatemia is known to stimulate 1,25-dihy- droxyvitamin D [1,25(OH)2D] production and in- more, FGF23 was shown to reduce the expression crease serum 1,25(OH)2D level. However, serum level of 25-hydorvitamin D-1α-hydroxylase which 1,25(OH)2D remains to be low to low normal indicat- ing that both phosphate reabsorption and vitamin D mediates the synthesis of 1,25(OH)2D. In addition, metabolism are deranged in these hypophosphatemic FGF23 increases the expression of 25-hydorvitamin diseases. D-24-hydroxylase, one of whose function is to degrade After cloning of FGF23, actions of FGF23 were ex- 1,25(OH)2D into more hydrophilic metabolites [8]. amined in vivo using recombinant FGF23. FGF23 was By altering the expression levels of these enzymes shown to suppress expression levels of type 2a and 2c involved in vitamin D metabolism, FGF23 reduces sodium-phosphate cotransporters in proximal tubular serum 1,25(OH)2D level. Because 1,25(OH)2D stimu- cells [8]. These transporters mediate physiological lates intestinal phosphate absorption, FGF23 reduces phosphate reabsorption and proximal tubular phos- serum phosphate level by inhibiting proximal tubular phate reabsorption is the main determinant of serum phosphate reabsorption as well as suppressing intesti- phosphate level at least in a chronic state. Further- nal phosphate absorption through decreased circulatory level of 1,25(OH)2D. ENDOCRINE FIBROBLAST GROWTH FACTORS 25 FGF23 and hypophosphatemic rickets/osteomalacia controls [19]. These results could be explained by regulatory production of FGF23. Several studies indi- As expected from actions of FGF23 in vivo, ADHR, cated that FGF23 production is tightly regulated. For ARHR, XLH, TIO and hypophosphatemic rickets/os- example, low phosphate diet lowers and high phos- teomalacia in MAS/FD have been shown to be caused phate diet increases serum FGF23 [20]. 1,25(OH)2D by excess actions of FGF23 (Table 2). Actually, the also increases circulatory FGF23 [21] and hyperphos- establishment of enzyme-linked immunosorbent assay phatemia was shown to be associated with high FGF23 for FGF23 indicated that circulatory levels of FGF23 [22]. Therefore, it may not be surprising that FGF23 are high in most of these patients [9–11]. The respon- levels are not high in patients with ADHR because hy- sible genes for XLH and ARHR are phosphate-regu- pophosphatemia or other associated metabolic changes lating gene with homologies to endopeptidases on the suppress expression of FGF23 even though mutant X chromosome (PHEX) [12] and dentin matrix protein FGF23 protein is resistant to the processing. In con- 1 (DMP1) [13, 14], respectively. Although the precise trast, it has been also shown that serum phosphate mechanism is unknown, model mice for XLH and level changes with time and high FGF23 level is asso- DMP1 knockout mice show enhanced expression of ciated with hypophosphatemia in patients with ADHR FGF23 in bone [13–15]. These results suggest that [19]. Therefore, it is likely that regulatory mecha- PHEX and DMP1 proteins are involved in the regula- nisms of FGF23 production are somehow deranged in tion of FGF23 expression in bone. Similarly, overex- these patients although the relationship between muta- pression of FGF23 in bone including regions affected tions in FGF23 gene and the regulation of FGF23 pro- by FD has been reported in patients with MAS/FD, duction is unclear. although the relationship between mutations in GNAS gene and overproduction of FGF23 remains unclear Physiological role of FGF23 [10]. TIO has been shown to be caused by overpro- duction of FGF23 in tumors responsible for TIO [7]. In addition to participate in the development of sev- Therefore, ARHR, XLH, hypophosphatemic rickets/ eral hypophosphatemic diseases, FGF23 is a physio- osteomalacia in MAS/FD and TIO are caused by ex- logical regulator of serum phosphate and 1,25(OH)2D cess production of FGF23 either in bone or tumors levels. FGF23 knockout mice show hyperphos- causing TIO. On the other hand, several studies have phatemia, enhanced proximal tubular phosphate reab- indicated that bone, especially osteocyte, is a physio- sorption, increased 1,25(OH)2D production and high logical source of FGF23 in addition to making excess 1,25(OH)2D