Source Of Fibroblast Growth Factor 23 Research Articles

A case of tumor-induced osteomalacia masked by acute kidney injury

Introduction:Hypophosphatemia in patients with tumor-induced osteomalacia (TIO) is due to abnormal excess production of fibroblast growth factor 23 (FGF-23) causing urinary phosphate wasting. However, in patients with coexisting acute kidney injury (AKI), hypophosphatemia may not be apparent as AKI reduces filtration and excretion of phosphate.Case report:We describe a case of 36-year-old woman who presented with right-sided abdominal pain. Initial laboratory testing revealed non oliguric AKI with creatinine (Cr) of 2.0 mg/dL (baseline 1.2 mg/dL), low phosphate (1.8 mg/dL), and normal parathyroid (PTH) levels. Hypophosphatemia in the setting of AKI and normal PTH raised suspicion for renal phosphate wasting disorder independent of PTH, triggering an order for FGF-23 level. Further into hospital stay, the AKI worsened (Cr rose to 7.2 mg/dL) and phosphate levels increased to 6.7 mg/dL casting doubt on the initial suspicion. However, FGF-23 level resulted at 12,715 RU/mL, strongly suggesting TIO. Random liver biopsy was obtained as part of TIO work up due to liver ultrasound findings of hepatomegaly, diffuse parenchymal heterogenicity mimicking steatosis and potential ill-defined mass. Liver specimen showed tumor cells positive for CD56 and Ki-67, indicating high-grade metastatic neuro endocrine tumor which was the likely source of FGF-23. Patient rapidly deteriorated and opted for comfort measures.Conclusion:TIO typically manifests with overt hypophosphatemia. This case highlights the fact that decreased glomerular filtration rate may mask the degree of urinary phosphate wasting resulting in normal to high serum phosphate level. This warrants high index of suspicion to diagnose an underlying phosphate wasting disorder in the setting of normal to high serum phosphate levels and reduced kidney function.

Mouse liver injury induces hepatic macrophage FGF23 production.

Fibroblast growth factor 23 (FGF23) is a bone marrow cell produced hormone that functions in the intestine and kidney to regulate phosphate homeostasis. Increased serum FGF23 is a well-established predictor of mortality in renal disease, but recent findings linking increased levels to hepatic and cardiac diseases have suggested that other organs are sources of FGF23 or targets of its effects. The potential ability of the liver to produce FGF23 in response to hepatocellular injury was therefore examined. Very low levels of Fgf23 mRNA and FGF23 protein were detected in normal mouse liver, but the amounts increased markedly during acute liver injury from the hepatotoxin carbon tetrachloride. Serum levels of intact FGF23 were elevated during liver injury from carbon tetrachloride. Chronic liver injury induced by a high fat diet or elevated bile acids also increased hepatic FGF23 levels. Stimulation of toll-like receptor (TLR) 4-driven inflammation by gut-derived lipopolysaccharide (LPS) underlies many forms of liver injury, and LPS induced Fgf23 in the liver as well as in other organs. The LPS-inducible cytokines IL-1β and TNF increased hepatic Fgf23 expression as did a TLR2 agonist Pam2CSK3. Analysis of Fgf23 expression and FGF23 secretion in different hepatic cell types involved in liver injury identified the resident liver macrophage or Kupffer cell as a source of hepatic FGF23. LPS and cytokines selectively induced the hormone in these cells but not in hepatocytes or hepatic stellate cells. FGF23 failed to exert any autocrine effect on the inflammatory state of Kupffer cells but did trigger proinflammatory activation of hepatocytes. During liver injury inflammatory factors induce Kupffer cell production of FGF23 that may have a paracrine proinflammatory effect on hepatocytes. Liver-produced FGF23 may have systemic hormonal effects as well that influence diseases in in other organs.

Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury.

Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.

Abstract 15231: Oncostatin M Receptor Deletion Decreases FGF23 After Transaortic Constriction in Mice and Receptor Activation Correlates With Increased FGF23 in Patients With Aortic Stenosis

Objectives: Fibroblast growth factor 23 (FGF23) is becoming increasingly recognized as biomarker for heart failure (HF). We have previously shown that oncostatin M (OSM) is the strongest cytokine which induces FGF23 secretion from cultured cardiomyocytes. Although the bone is regarded as the source of FGF23, we have also demonstrated that cardiomyocytes of patients with end-stage HF strongly express FGF23. In this study we tested the hypothesis that the hypertrophied, non-failing heart is a source of circulating FGF23 via OSM receptor (Oβ) activation. Methods: Transaortic constriction (TAC) was performed in WT and Oβ knock-out mice (OβKO). Sham operated mice served as control. We have analysed myocardial biopsies and serum from patients with aortic stenosis (AS) with preserved ejection fraction. Patients with kidney disease were excluded from the study. Serum from healthy volunteers served as a control. Proteome and transcriptome profiling of serum and tissue samples in mice and AS patients were performed by mass spectrometry, multiplex assays, RT-PCR, ELISA, confocal microscopy (CM) and Western blots (WB). Results: Four weeks after TAC, WT mice animals showed significant increases in circulating FGF23 in comparison to sham-operated mice (583±117 (n=10) vs 218±36 pg/mL (n=10); p&lt;0.05). Furthermore, CM, WB and RT-PCR analysis consistently revealed up-regulation of FGF23 expression and increased Oβ mRNA levels (100±10% (n=8) vs 284±26% (n=8); p&lt;0.01) in cardiomyocytes. Conversely, TAC-OβKO showed reduction of circulating FGF23 to Sham levels (215±39 pg/mL (n=11); p&lt;0.02) and significantly decreased myocardial FGF23 expression as compared to TAC in WT mice. Similarly, AS patients showed a 2.7-fold higher expression of Oβ in comparison to control tissue (269±77 (n=8) vs 100±28% (n=4); p&lt;0.05). FGF23 serum levels were elevated 4-fold in comparison to serum from volunteers (85±47 (n=19) vs 23±2 (n=16) RU/mL; p&lt;0.01). Conclusions: Our data demonstrate that Oβ activation is responsible for the cardiac release of FGF23 into the circulation in TAC animals. Activation of Oβ and increased levels of FGF23 in patients with AS indicates that FGF23 is a potential biomarker in AS patients with compensated hypertrophy before the onset of HF.

RAS in FGF23: Another Piece in the Puzzle

The first piece of the puzzle that is the evolving story of fibroblast growth factor-23 (FGF23) physiology was identified in 1959 by Andrea Prader (1). He postulated the existence of a phosphate-regulating hormone as the cause of acquired rickets in a child who was cured by excision of a bone-derived tumor. More pieces were added in 1976, 1989, and 1992, respectively, by the discovery of the Hyp mouse as a model of X-linked hypophosphatemic rickets (XLH) and elegant parabiosis and renal transplant studies in hyp mice that clearly demonstrated that a circulating factor was responsible for the phosphate wasting in Hyp mice (2,–4). A key piece was identified in 2000 when the autosomal dominant hypophosphatemic rickets (ADHR) consortium discovered that mutations in FGF23 were responsible for ADHR (5). In rapid succession, FGF23 was found to be elevated in patients with XLH, tumor-induced osteomalacia, and fibrous dysplasia (FD) of bone (6, 7). Another important piece was added when it was discovered that bone-derived cells were the source of FGF23, not only in the dysplastic bone cells of FD but also in normal bone (7).

Fibroblast Growth Factor 23 and Klotho Are Present in the Growth Plate

Introduction: Regulation of phosphate homeostasis is essential for mineralization and enchondral ossification. Fibroblast growth factor 23 (FGF23) and its obligatory co-receptor Klotho (KL) play a key role in this process by influencing both renal phosphate reabsorption and vitamin D metabolism. In disease, excessive action of FGF23 leads to hypophosphatemic rickets, while its deficiency causes tumoral calcinosis. Although osteocytes and osteoblasts are widely seen as the primary source of FGF23 under physiological conditions, the origin of systemic FGF23 remains controversial. In this study, we investigated the expression of FGF23 and KL in porcine growth plate cartilage, adjacent tissues, and parenchymal tissues.Materials and Methods: Tissue samples were obtained from 4- to 6-week-old piglets. mRNA expression was quantified by real-time PCR and normalized to 18S rRNA. Immunohistochemical staining was performed for FGF23, KL, collagen type X, and FGF receptor 1. Growth plate chondrocyte subpopulations were acquired by collagenase digestion of growth plate explants and subsequent density gradient centrifugation.Results: We could detect both FGF23 and KL mRNA and protein in growth plate chondrocytes. FGF23 expression was mainly found in hypertrophic and resting chondrocytes. Furthermore, significant expression of both genes was observed in bone, liver, and spleen.Conclusion: These data challenge previous expression analyses, in particular theories of bone as the exclusive source of FGF23. Moreover, significant expression of FGF23 and KL within the growth plate and adjacent tissues imply a potential local role of FGF23 in chondrocyte differentiation and tissue mineralization.

Repeated Venous Sampling for Determination of a Gradient of Fibroblast Growth Factor 23 for Localization of an Osteomalacis Causing Tumor

Background: Oncogenic osteomalacia (OOM) is a rare syndrome caused by a tumor that produces a phosphaturic factor: fibroblast growth factor 23 (FGF23). These tumors can be extremely difficult to localize because they are small, slow growing and cause no local Symptoms. Patient and methods: Venous sampling for detection of a gradient of FGF23 has been used to limit the area of further imaging. We describe a case of OOM in a 73-year old woman, with two years of spontaneous fractures, severe musculoskeletal pain and phosphate wasting. Results: Her scrum FGF23 level was increased and whole-body intravenous sampling (11 sites) revealed a FGF23 gradient from the right leg. The second sampling indicated that the source of FGF23 was below the knee, but imaging studies, including magnetic resonance imaging and octreotide scintigraphy, were not conclusive. A third sampling demonstrated increasing FGF23 the more distal one came in the lower leg. Imaging of the forefoot finally identified a 10 mm tumor that was removed. Histopathological examination showed a phosphaturic mesenchymal tumor of mixed connective tissue type. The phosphate level and symptoms improved in days after surgery. Conclusion: Repeated determinations of a venous gradient of FGF23 may be used to localize tumors of OOM.

New Insights into the Roles of Fibroblast Growth Factor 23

Fibroblast growth factor 23 (FGF23) is expressed primarily in skeletal tissues including osteoblasts/osteocytes and acts as a hormone regulating phosphate and vitamin D homeostasis. An excess of active FGF23 in the circulation causes multiple anomalies seen in phosphaturic diseases including rickets/osteomalacia, consistent with some but not all of the phenotypic anomalies seen in FGF23 deficient mice. FGF23 is targeted to kidney and negatively regulates activity/expression of the type II sodium-phosphate cotransporter (NPT2) as well as 25-hydroxy vitamin D-1α-hydroxylase in proximal tubular cells. Recently, teeth have been identified as a possible second principle source of FGF23. Further, both the parathyroid and bone also appear to be functional targets of FGF23: the polypeptide decreases parathyroid hormone (PTH) production and suppresses bone formation in vitro, suggesting a new dimension of FGF23 biology in development and homeostasis. In contrast to other FGF family members, FGF23 requires Klotho, a senescence-related type I membrane protein, for its specific signaling in target organs. However, Klotho expression has not yet been confirmed in skeletal tissues. Nevertheless, similarly to FGF2, FGF23 promotes FGFR1 phosphorylation whose signaling is involved in the negative regulation of bone formation. 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) is a potent regulator of FGF23 expression, closely correlated with its inhibitory effect on matrix mineralization. The cleaved extracellular domain of Klotho is known to act as a circulating factor. Therefore, FGF23 may be able to act on multiple tissues including skeletal tissues as a pleiotropic factor, coordinately with or without 1,25(OH)2D and PTH.

Regulation of Fibroblast Growth Factor-23 Signaling by Klotho

The aging suppressor gene Klotho encodes a single-pass transmembrane protein. Klotho-deficient mice exhibit a variety of aging-like phenotypes, many of which are similar to those observed in fibroblast growth factor-23 (FGF23)-deficient mice. To test the possibility that Klotho and FGF23 may function in a common signal transduction pathway(s), we investigated whether Klotho is involved in FGF signaling. Here we show that Klotho protein directly binds to multiple FGF receptors (FGFRs). The Klotho-FGFR complex binds to FGF23 with higher affinity than FGFR or Klotho alone. In addition, Klotho significantly enhanced the ability of FGF23 to induce phosphorylation of FGF receptor substrate and ERK in various types of cells. Thus, Klotho functions as a cofactor essential for activation of FGF signaling by FGF23.

Skeletal changes in epidermal nevus syndrome: Does focal bone disease harbor clues concerning pathogenesis?

Epidermal nevus syndrome (ENS) is a rare, sporadic, congenital disorder of unknown etiology featuring a complex and highly variable phenotype that can include focal or generalized skeletal disease. We describe a young man with ENS manifesting right-sided linear skin lesions, generalized weakness, diffuse osteopenia associated with hypophosphatemic rickets, and distinctive focal bone lesions ipsilateral to the skin findings. Review of the literature concerning ENS-associated skeletal disease suggested such focal bone defects are fibrous dysplasia, but our patient did not have the typical radiographic or histopathologic findings of fibrous dysplasia. Nevertheless, his circulating fibroblast growth factor 23 (FGF-23) level was elevated, likely functioning as a "phosphatonin," yet no activating mutations in GNAS previously reported in fibrous dysplasia or McCune-Albright syndrome were detected in his leukocytes or affected skin. We postulate that the focal skeletal disease, although different than fibrous dysplasia, may be a source of FGF-23 in ENS.