PHYSIOLOGY.ORG
Skip main navigation
ReviewInflammation and Inflammatory Mediators in Kidney Disease

Ironing out the cross talk between FGF23 and inflammation

Published Online:01 Jan 2017https://doi.org/10.1152/ajprenal.00359.2016

Abstract

The bone-secreted hormone fibroblast growth factor 23 (FGF23) has an essential role in phosphate homeostasis by regulating expression of the kidney proximal tubule sodium-phosphate cotransporters as well as parathyroid hormone levels. Induction of FGF23 early in chronic kidney disease (CKD) helps to maintain normal phosphorous levels. However, high FGF23 levels become pathological as kidney disease progresses and are associated with an increased risk of CKD progression, cardiovascular events, and death. The factors responsible for increasing FGF23 levels early in CKD are unknown, but recent work has proposed a role for inflammation and disordered iron homeostasis. Notably, FGF23 has recently been shown to elicit an inflammatory response and to display immunomodulatory properties. Here, we will review emerging evidence on the cross talk between inflammation, iron, FGF23, and bone and mineral metabolism and discuss the relevance for CKD patients.

fibroblast growth factor 23 (FGF23) is a circulating hormone mainly produced by osteocytes and osteoblastic cells (53). FGF23 primarily targets the kidney to decrease the sodium phosphate cotransporters NPT2a and NPT2c and to reduce 1,25-dihydroxyvitamin D [1,25(OH)2D] production by inhibiting the renal 1α hydroxylase (Cyp27b1) and stimulating the catabolic 24-hydroxylase (Cyp24a1) (Fig. 1) (17, 28). The net effect is to limit intestinal phosphate absorption and to inhibit renal phosphate reabsorption. FGF23 also targets the parathyroid gland to inhibit parathyroid hormone (PTH) secretion (5, 44). All of the hereditary and acquired disorders of excess FGF23 have overlapping clinical characteristics, including renal phosphate wasting, inappropriately low 1,25(OH)2D levels, and rickets/osteomalacia (65). In contrast, FGF23 deficiency results in hyperphosphatemia, moderate hypercalcemia, low PTH levels, markedly elevated 1,25(OH)2D levels, and soft tissue calcifications (75, 83).

Fig. 1.

Fig. 1.Fibroblast growth factor 23 (FGF23) and mineral metabolism. When serum levels of calcium decrease, secretion of parathyroid hormone (PTH) by the chief cells in the parathyroid gland increase renal reabsorption of calcium (Ca) and renal synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D]. PTH also decreases renal phosphate (Pi) reabsorption. 1,25(OH)2D stimulates intestinal absorption and renal reabsorption of calcium and phosphate. In return, 1,25(OH)2D and the consequent increased levels of calcium suppress PTH secretion. Excess PTH, 1,25(OH)2D, calcium, and phosphate stimulate intact FGF23 (iFGF23) production in bone. iFGF23 inhibits both PTH and 1,25(OH)2D production and suppresses renal phosphate reabsorption. The net result is a reduction in serum phosphate levels. To prevent the onset of severe hypocalcemia as a consequence of FGF23-mediated calciotropic hormone suppression, iFGF23 also increases renal calcium reabsorption. cFGF23, COOH-terminal FGF23.

Download figureDownload PowerPoint

Chronic kidney disease (CKD) is associated with high FGF23 levels. Clinical and animal studies have shown that FGF23 levels are elevated early during the course of renal failure in proportion to the decline in glomerular filtration rate, and increased FGF23 is the initial event leading to reductions in calcitriol and elevations of PTH in response to loss of renal function (38). Circulating FGF23 levels are also greatly increased in end-stage renal failure and correlate with the degree of hyperphosphatemia. In these settings, high FGF23 is proposed as a causal factor of left ventricular hypertrophy, and elevated FGF23 levels are associated with CKD progression and death (29, 37, 43, 63, 89, 97). Thus, understanding the precise mechanisms contributing to increased FGF23 levels in patients with CKD is of great clinical significance.

FGF23 Production and Cleavage

FGF23 has an NH2-terminal FGF homology domain for binding to FGF receptors (FGFRs) and a unique COOH-terminal domain that permits interaction with the coreceptor α-klotho, which facilitates FGF23-FGFR interactions (90). In circulation, FGF23 is detected as a full-length intact bioactive protein (iFGF23) and as cleaved fragments that are thought to be inactive (24, 36). The major forms of FGF23 fragments are the result of proteolytic cleavage by furin and furin-like proprotein convertases (6). FGF23 cleavage is assessed by measuring the abundance of the major fragments with the COOH-terminal FGF23 assay (cFGF23), which captures both iFGF23 and its COOH-terminal fragments, and comparing results with an assay that captures only iFGF23 (96). However, precisely quantitating COOH-terminal fragments and the ratio of cFGF23 to iFGF23 is limited by the fact that these assays report results using different units (pg/ml for iFGF23 and relative units/ml for cFGF23).

Circulating iFGF23 levels are tightly regulated at multiple levels by a balance between FGF23 transcription and FGF23 cleavage by both local and systemic factors (98). O-glycosylation at the cleavage site by UDP-N-acetyl-α-d-galactosamine-polypeptide N-acetylgalactosaminyl-transferase 3 protects FGF23 from cleavage and ensures its secretion (40, 88), whereas phosphorylation at the cleavage site by “family with sequence similarity 20, member C protein” inhibits O-glycosylation and promotes cleavage (85). CKD is also associated with an impairment in FGF23 cleavage that contributes to higher iFGF23 levels (16). Although the mechanisms remain unclear, this makes CKD patients susceptible to a more robust induction of iFGF23 levels in response to any stimulus that increases FGF23 production.

At the transcriptional level, FGF23 production is induced by elevations of PTH, phosphate, 1,25(OH)2D, and calcium (Fig. 1) (1, 15, 46, 50). However, although frequently associated with CKD, none of these classical factors explain the early increase in FGF23 seen in CKD patients, since elevations in FGF23 levels precede these other abnormalities in bone and mineral metabolism (38). More recently, multiple studies suggest that iron deficiency and systemic inflammation upregulate FGF23 production (Fig. 2) (16, 24). Notably, iron deficiency and inflammation also upregulate FGF23 cleavage, so that they do not much impact iFGF23 levels in the acute setting (16, 36). However, these stimuli can increase iFGF23 levels when FGF23 cleavage is reduced, for example, in patients with autosomal dominant hypophosphatemic rickets with mutations in FGF23 that impair cleavage (36) or in animal models of CKD (16). Iron deficiency and inflammation are also commonly associated with CKD and therefore may contribute to elevated iFGF23 levels in this patient population (51, 94, 95). Interestingly, elevated FGF23 has also been shown to elicit an inflammatory response (30) and to display immunomodulatory properties (68). This constitutes a novel and important field of FGF23 research, which we further discuss in this review.

Fig. 2.

Fig. 2.FGF23 and inflammation. The onset of inflammation increases the secretion of the hepatic iron regulatory hormone hepcidin, which induces degradation of the iron export protein ferroportin, leading to increased iron retention in enterocytes and macrophages. The net result is a reduction of circulating iron levels. The consequent iron deficiency stimulates FGF23 production and cleavage. Increased renal erythropoietin (EPO) production in response to iron deficiency will also further stimulate FGF23 production. Finally, inflammatory cytokines will directly stimulate osseous FGF23 production and cleavage. The end effect of inflammation is mildly increased iFGF23 and very high cFGF23 levels. In return, iFGF23 stimulates renal and hepatic inflammation and leads to other immunomodulatory effects.

Download figureDownload PowerPoint

Inflammation: Bone and Mineral Metabolism

Inflammation and bone.

Although inflammation can affect almost any organ of the body, even low-level subclinical inflammation has been reported to affect bone remodeling and increase fracture risk (71). The nature of the inflammatory disorder determines the extent and type of bone disease, but most of these diseases display common mechanisms and lead to similar consequences. While inflammation may have indirect effects on bone metabolism by modulating the levels of reproductive hormones (2, 4), the secretion and action of PTH, and vitamin D (8, 69), inflammation also directly affects bone resorption and bone formation by acting on the bone-remodeling cycle.

Acute and chronic inflammation modify bone and mineral metabolism differently. Most commonly, acute inflammation increases bone remodeling, and both bone resorption and formation are increased. Chronic inflammatory diseases result in an uncoupling of bone formation from resorption in favor of excess resorption. Most proinflammatory cytokines have direct stimulatory effects on osteoclastogenesis, including TNF-α, interleukin (IL)-1β, IL-6, IL-11, and IL-17, which can synergize to directly potentiate bone resorption by osteoclasts (42, 86). Indeed, IL-1β, one of the earliest pathophysiological processes involved during inflammation, was initially named osteoclast-activating factor due to its pro-osteoclastogenic and resorptive properties (19). The tight coupling of bone resorption and formation results secondarily in a stimulation of bone formation during acute inflammation. However, during chronic inflammation, bone formation is suppressed or remains inappropriately normal. Although the mechanisms involved in the uncoupling remain uncertain, a suppression of Wnt and alteration of glucocorticoid signaling in osteoblasts seem to be the major causes of an altered bone formation (12, 56, 87).

Inflammation and phosphate.

Phosphate and vitamin D, which are both targets and regulators of FGF23, are also closely associated with systemic inflammation. High serum phosphate is independently associated with inflammatory markers such as IL-6 (60), and dietary Pi loading dose dependently induces inflammation and increases serum TNF-α levels in uremic rats (99). In contrast, restriction of gut phosphorus absorption reduced biomarkers of inflammation in CKD patients, indicating that excess phosphorus intake is proinflammatory. Interestingly, hypophosphatemia is associated with sepsis, and the degree of hypophosphatemia correlates with sepsis severity (72, 73). Thus, alterations in phosphate levels are associated with changes in the inflammatory response, although a full understanding of the relationship between phosphate and inflammation requires further clarification.

Inflammation and vitamin D.

Mainly known for its effects on mineral metabolism and bone mineralization, poor vitamin D status has been associated with multiple immune-mediated disorders and inflammatory diseases, including rheumatoid arthritis, lupus, inflammatory bowel disease, and type 1 diabetes. The actions of vitamin D are complex and affect both innate and adaptive immune systems to reduce inflammation, promote immune tolerance, and enhance antimicrobial responses. Specifically, vitamin D induces antimicrobial peptide synthesis (93), triggers the expression of inducible nitric oxide synthase (67), represses the expression of Toll-like receptors (TLRs) (48), and inhibits the production of proinflammatory cytokines by innate immune cells (77). In addition, vitamin D receptor activation inhibits dendritic cell differentiation and maturation, as shown by decreased maturation-induced surface markers. Consequently, an inverse relation has been shown between vitamin D concentrations and C-reactive protein, a marker of inflammation, in both healthy subjects and patients with rheumatoid arthritis and frailty (61, 64).

Regulation of renal calcitriol production by inflammatory stimuli is disputed. However, immune cells synthetize 1,25(OH)2D. Cyp27b1, the enzyme catalyzing the hydroxylation of 25-hydroxyvitamin D (25OHD) to 1,25(OH)2D, is expressed in T cells, activated macrophages, and dendritic cells, and Cyp27b1 is under the control of immune stimuli. In contrast, Cyp24a1, the 25OHD and 1,25(OH)2D catabolizing enzyme, is transcribed as an inactive splice variant in immune cells, which prevents the local breakdown of 25OHD and 1,25(OH)2D and exposes cells to higher concentrations of vitamin D. This suggests that local vitamin D status is a target of inflammation in addition to its immunomodulatory effects.

Inflammation Regulates FGF23 Metabolism

Inflammation increases FGF23 production.

Increased iFGF23 and cFGF23 levels are independently associated with higher levels of inflammatory markers in patients with CKD (52, 57). In addition, FGF23 levels correlate with (17) markers of inflammation in other inflammatory diseases (20, 32, 34, 57, 70). For example, iFGF23 was raised in the serum of patients with juvenile systemic lupus erythematosus (54) and in the cartilage of patients with rheumatoid arthritis (35). iFGF23 was also increased during flares in patients with inflammatory bowel disease and was reduced in remission (21).

In bone and osteoblast/osteocyte cell lines, inflammatory cytokines directly induce FGF23 production. In a differentiated IDG-SW3 osteocytic cell line, treatment with TNF, IL-1β, TNF-related weak inducer of apoptosis, or lipopolysaccharide triggered a rapid increase in FGF23 expression (39). Indeed, FGF23 mRNA was increased 3 h poststimulation in these cells. A similar response was seen in cultured human trabecular bone chips, suggesting that induction of FGF23 production by inflammation is model independent. More recently, we have shown that MC3T3 murine osteoblasts also directly respond to IL-1β by increasing FGF23 transcription and secretion. In vivo, in two different mouse models of acute inflammation due to administration of either heat-killed Brucella abortus or IL-1β, we reported a 10-fold increase in Fgf23 mRNA expression 6 h posttreatment and a comparable increase in circulating total cFGF23 levels (16). These data demonstrate that inflammatory cytokines are direct regulators of FGF23 production in bone and suggest that osseous FGF23 production is at least in part responsible for the increase in circulating FGF23 levels.

It is interesting to note that local production of FGF23 occurs in the heart in models of cardiac hypertrophy, suggesting that, in addition to high circulating levels, local cardiac FGF23 might be involved in left ventricular hypertrophy. FGF23 production also increases in response to inflammation in cardiac fibroblasts (101). How extraosseous FGF23 might contribute to circulating levels of FGF23 is still unknown.

Inflammation controls FGF23 cleavage.

Although inflammation induces a remarkable increase in bone FGF23 mRNA and protein expression as well as high circulating cFGF23 levels, the circulating levels of iFGF23 remain unaltered in the acute setting and only mildly induced in the chronic settings (16). This differential response is triggered in both cell culture and in vivo models by a concomitant increase in FGF23 cleavage (16, 39). We and others have found that cotreatment of cells and animals with furin/furin-like protease inhibitors and inflammatory cytokines resulted in the upregulation of secreted iFGF23. Furin inhibition did not further increase Fgf23 mRNA expression or circulating cFGF23 in vivo and did not affect Fgf23 promoter activity in the MC3T3 osteoblast-like cell line in vitro (16). However, inhibition of cleavage did significantly increase intracellular and secreted iFGF23 in IL-1β-treated cells as opposed to controls only receiving IL-1β (16). These observations demonstrate that FGF23 cleavage by furin/furin-like proteases is a key factor in maintaining normal levels of biologically active iFGF23 levels (16, 39). The concomitant increase in FGF23 transcription and cleavage peaks during acute inflammation, and both are markedly reduced during chronic inflammation. Most interestingly, FGF23 proteolytic cleavage is decreased to a greater extent than FGF23 transcription during chronic inflammation, ultimately leading to a slight increase in iFGF23 (16). The uncoupling between FGF23 transcription and cleavage during chronic inflammation suggests that either the amount of newly produced FGF23 saturates the cleavage capabilities within osteocytes or that an active mechanism inhibiting cleavage is triggered. Additional studies are necessary to discriminate between the effects of chronic and acute inflammation on FGF23 production and cleavage.

Mechanisms for FGF23 Regulation by Inflammation

Given the dramatic effects of inflammation on bone and mineral metabolism, the increase in FGF23 may occur in response to modifications of systemic and/or local regulators of FGF23. Hyperparathyroidism, often associated with inflammatory cytokines, and increased local production of 1,25(OH)2D by inflammatory cells might elicit an increase in FGF23 transcription (46, 50). Release of minerals such as calcium and phosphate from the bone by overactive osteoclasts is also a possible indirect mechanism of increased FGF23 production (15). Similarly, release from the bone matrix during bone resorption of other paracrine FGFs, which increase FGF23 transcription (31), or FGF23 itself (100), could contribute to the increase in circulating FGF23 levels. In support of this, patients with excessive bone resorption show increased FGF23 circulating levels, and inhibition of bone resorption by treatment with pamidronate normalizes FGF23 levels (41). Inflammation also affects to various degrees the expression of known negative regulators of FGF23 transcription such as Phex and Dmp1. Indeed, mRNA expression of these factors is suppressed by proinflammatory cytokines, concomitant with an increase in Fgf23 mRNA (39). Finally, inflammation induces a state of functional iron deficiency where circulating iron levels are low despite adequate body iron stores due to iron sequestration in the reticuloendothelial system (Fig. 2) (16). This functional iron deficiency is caused by inflammatory cytokine-mediated induction of the iron regulatory hormone hepcidin, which induces degradation of the iron export protein ferroportin (92). True iron deficiency, where both circulating and stored iron levels are low, is strongly associated with increased FGF23 production and cleavage, both in humans and animal models (16, 24, 36). Notably, injection of exogenous hepcidin, which causes functional iron deficiency in the absence of systemic inflammation, similarly increases FGF23 production and cleavage to some extent, suggesting that functional iron deficiency per se may contribute to FGF23 induction by inflammation in vivo, similar to the effects of true iron deficiency (16). Nevertheless, these alterations do not explain the rapid increase in FGF23 production and secretion of cFGF23 in osteoblastic cell cultures treated with inflammatory cytokines, which suggest the existence of additional direct cellular effects (16, 39).

Three major signaling pathways have been described as essential to the induction of FGF23 production during inflammation (Fig. 3). The most recently described is the calcineurin/nuclear factor of activated T cells (NFAT) pathway (31), which is also responsible for klotho-independent FGF23 signaling in the heart (25, 27) and parathyroid gland (62). There is a NFAT response element (RE) on Fgf23 proximal promoter, and the NfatRE is essential in the FGF23 response to calcium and paracrine FGFs (31).

Fig. 3.

Fig. 3.Molecular mechanisms regulating FGF23 production in response to inflammation. The onset of inflammation results in markedly decreased serum iron levels. Inflammation and iron deficiency lead to an increase in hypoxia-inducible factor (HIF)-1α expression or stabilization. Transcriptionally active HIF-1α/HIF-1β heterodimers translocate to the nucleus and bind hypoxia-responsive elements (HRE) to upregulate Fgf23 expression. Inflammation also activates nuclear factor κ-light chain enhancer of activated B cells (NF-κβ), and nuclear factor of activated T cells (NFAT), which translocate to the nucleus, bind to response elements (RE) in the FGF23 promoter, and activate its transcription. In addition, inflammation and iron deficiency also stimulate Fgf23 transcription through alternate mechanisms that are not yet understood.

Download figureDownload PowerPoint

The “canonical” inflammatory signaling pathway, nuclear factor κ-light chain enhancer of activated B cells (NF-κB) is also a contributor to the FGF23 induction by inflammation. Indeed, NF-κB activation markedly increased FGF23 transcription, whereas NF-κB inhibition reduced FGF23 response to inflammatory stimuli (39). However, a 50- to 100-fold increase in Fgf23 transcription remained unaccounted for even after NF-κB inhibition, and activation of NF-κB does not explain the concomitant increase in FGF23 cleavage observed during inflammatory settings (39).

The similarities between the FGF23 response to inflammation and those observed during iron deficiency, namely a concomitant increase in FGF23 transcription and cleavage, suggest that inflammation may affect FGF23 production and cleavage directly through cytokine-mediated mechanisms similar to those encountered during iron deficiency. Indeed, we showed that treatment with deferoxamine, an iron chelator, increased Fgf23 mRNA expression in bone marrow stromal cells or the MC3T3-E1 osteoblast-like cell line, similar to the treatment of cell cultures with IL-1β (16). One common mechanism between hypoferremia and inflammation is activation of hypoxia inducible factor (HIF)-1α (10, 16, 24). A decrease in cellular iron increases Hif-1α nuclear abundance by promoting the normoxic stabilization of HIF-1α protein through inhibition of prolyl hydroxylase activity and HIF-1α degradation, without affecting Hif-1α mRNA expression (16). Inflammatory disease states are frequently characterized by tissue hypoxia and increases in expression or stabilization of hypoxia-dependent transcription factors, such as HIF-1α (23). NF-κB is also a critical transcriptional activator of HIF-1α (66), and HIF-1α activation directly induces NF-κB (13) and indirectly amplifies NF-κB activation by increasing the expression and signaling of TLRs (45). The increase in HIF-1α nuclear abundance is thought to dampen excessive inflammation and increase ischemia tolerance.

In support of an active role for HIF-1α in FGF23 production, we and others have shown that activation of Hif-1α in bone cells induces FGF23 transcription and cleavage (10, 16, 24). We have also shown that administration of two HIF-1α inhibitors decreased both Fgf23 mRNA levels and circulating cFGF23 levels in response to IL-1β in mice (16). In contrast, injection of two prolyl-hydroxylase inhibitors that activate HIF-1α induced Fgf23 mRNA expression and circulating cFGF23 in mice (16). Thus, HIF-1α activation in bone coordinates both FGF23 production and cleavage. Although the exact HIF-1α-mediated mechanisms leading to FGF23 cleavage are not fully elucidated, it is possible that coactivation of furin by HIF-1α limits the secretion of biologically active FGF23 (10, 16, 24, 98). Indeed, coadministration of furin inhibitors to mice injected with prolyl-hydroxylase inhibitors increased iFGF23, suggesting that HIF-1α controls the expression and/or activity of furin or furin-like proteases (16).

In addition to HIF-1α-dependent pathways in osteoblasts and osteocytes that control FGF23 production and metabolism, recent evidence has emerged showing that systemic extraosseous upregulation of HIF might also play an important role in FGF23 production. Indeed, upregulation of HIF in the kidneys will drive secretion of erythropoietin (EPO), which dose dependently increases FGF23 mRNA and total protein (9). This might further explain the adverse effects of EPO or erythropoiesis stimulating agents during the course of CKD progression (47, 82, 84). This also suggests that multiorgan normoxic and hypoxic HIF-1α stabilization occurring in CKD might represent an alternative therapeutic target. Interestingly, FGF23 was recently reported to reduce EPO production, whereas Fgf23−/− mice have increased EPO levels (11), suggesting that there may be a negative feedback loop between these two pathways.

FGF23 as a Proinflammatory and Immune-Modulatory Hormone

Although the majority of circulating FGF23 is of osseous origin, FGF23 is also physiologically expressed in organs involved in the immune system, including thymus and spleen (49). At a cellular level, dendritic cells and macrophages express FGF23 and increase their production during inflammation (55) and macrophage polarization (30). FGF23 production has also been shown to occur in clonal lymphocytes and plasma cells in patients with B cell neoplasms, including plasma cell dyscrasias (81) and B cell non-Hodgkin's lymphoma (22). In this context, cFGF23 is elevated in circulation, although iFGF23 remains in the normal range in the majority of cases.

Why is FGF23 produced by immune cells, and why is it induced by inflammation? At the present time, the physiological role(s) of FGF23 in regulating inflammation and the immune response are poorly understood. The simplest explanation is that FGF23 modulates the excess calcium and phosphate released from bone due to inflammation-enhanced bone resorption. Indeed, reduction of vitamin D and inhibition of renal sodium phosphate cotransporters will ensure that serum calcium and phosphate levels will remain close to normal. Emerging evidence also suggests that local and systemic FGF23 may have a pathological role under conditions of chronic FGF23 excess. One mechanism may be indirect, through FGF23 effects on modulating levels of vitamin D, which has a crucial role in innate immune responses and inflammation. FGF23 not only reduces the circulating levels of calcitriol but it also reduces the local conversion of 25OHD to 1,25(OH)2D by monocytes and dendritic cells by inhibiting expression of both Cyp27b1 and the alternatively spliced Cyp24a1 (3). Thus, by reducing vitamin D levels, chronic FGF23 excess may have a proinflammatory effect and may increase susceptibility to infections.

There is also evidence for a direct role of FGF23 in mediating inflammatory responses (14, 30, 68). Indeed, FGF23 directly promotes TNF-α production independent of klotho in splenocytes (91) and macrophages (30, 55). We have previously shown that, in CKD, FGF23-responsive genes in the kidney were of a proinflammatory nature (14), including those involved in TGF-β, TNF-α, and IL-1β signaling pathways. This suggests that excess FGF23 might accentuate the progression of renal disease and other adverse outcomes through its proinflammatory properties. A proinflammatory role for FGF23 has also been recently shown in hepatocytes (76). Interestingly, these proinflammatory responses were mediated by signaling through FGFR4 (76), the klotho-independent pathway responsible for FGF23's adverse effects in the heart (27).

FGF23 has also been proposed to have a variety of other effects on immune cell function and host defense. High doses of FGF23 increase the number of macrophages (55) and induce proliferation of murine bone marrow-derived pro-B cell lines (102), whereas Fgf23-null mice display an atrophy of the thymus (58), a reduced number of splenocytes and lymph nodes, and decreased capacity for T cell proliferation. More recently, FGF23 has been shown to signal via FGFR2 in neutrophils to inhibit β2-integrin activation, thereby reducing adhesion and transendothelial migration (68). Importantly, FGF23 excess due to CKD or exogenous administration was shown to inhibit leukocyte recruitment in the lung and increase mortality from pneumonia in mice, effects that were reversed by administration of a neutralizing FGF23 antibody (68). Similar findings were reported in ex vivo experiments using leukocytes from CKD patients. These data suggest that FGF23 excess may directly contribute to the acquired immune deficiency syndrome in CKD patients.

Taken together, current data suggest that excess FGF23 in CKD may have a dual effect to promote inflammation and impair the immune response, through both direct effects and indirectly by reducing vitamin D. Because chronic inflammation is associated with numerous adverse outcomes (7, 18, 33, 74, 78–80) and infectious complications are important causes of morbidity and mortality in CKD patients (59), these proinflammatory and immune-modulatory properties of FGF23 may explain at least part of the associations between FGF23 excess and negative outcomes in CKD patients (26, 29).

Interestingly, the balance between FGF23 production and cleavage in these circumstances may be of crucial importance. Most of the direct and indirect proinflammatory and immunomodulatory effects are attributed to the intact FGF23 hormone. Thus, the physiological balance between production and cleavage in patients and animals with intact kidney function may help minimize the negative effects of excess FGF23 secretion. However, it is also possible that the small COOH and NH2 FGF23 peptides, while ineffective in controlling phosphaturia and vitamin D metabolism, may have a role in modulating inflammatory mechanisms. First, COOH-terminal FGF23 peptides, containing the α-klotho-binding domain, could act as a decoy receptor for soluble and membrane-bound α-klotho, thus reducing the effects of both klotho and iFGF23. Second, NH2-terminal FGF23 peptides, containing the FGFR-binding motif, could act as paracrine FGFs activating specific FGFR signaling. Although a functional role for COOH- and NH2-terminal FGF23 peptides is purely speculative and will require further study, this could explain why FGF23 production and cleavage are induced by inflammation with minimal impact on iFGF23 levels (16, 39).

Conclusion

Recent studies have revealed a complex relationship between FGF23 and inflammation. FGF23 expression and cleavage are upregulated by inflammation, and FGF23 in turn possesses proinflammatory and immune-modulatory properties. These studies may have important implications for CKD patients, who have markedly elevated FGF23 levels and are often in a state of chronic inflammation. Future studies are needed to understand fully the molecular mechanisms by which inflammation regulates FGF23 expression, the physiological role of FGF23 in inflammation and the immune response, and to what extent these proinflammatory and immune functions of FGF23 may have a role in the adverse outcomes associated with high FGF23 levels in CKD patients.

GRANTS

This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-102815 to V. David and R01-DK-087727 to J. L. Babitt and by a Howard Goodman Fellowship Award from the Massachusetts General Hospital to J. L. Babitt.

DISCLOSURES

V. David receives research support from Keryx Biopharmaceuticals. J.L. Babitt has ownership interest in Ferrumax Pharmaceuticals, Inc. C. Francis has no conflict of interest to disclose.

AUTHOR CONTRIBUTIONS

V.D. and J.L.B. drafted manuscript; V.D., C.F., and J.L.B. edited and revised manuscript; V.D., C.F., and J.L.B. approved final version of manuscript; C.F. prepared figures.

REFERENCES

  • 1. Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab 91: 3144–3149, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 2. Arlt W, Hammer F, Sanning P, Butcher SK, Lord JM, Allolio B, Annane D, Stewart PM. Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock. J Clin Endocrinol Metab 91: 2548–2554, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 3. Bacchetta J, Sea JL, Chun RF, Lisse TS, Wesseling-Perry K, Gales B, Adams JS, Salusky IB, Hewison M. Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes. J Bone Miner Res 28: 46–55, 2013.
    Crossref | PubMed | Web of Science | Google Scholar
  • 4. Beishuizen A, Thijs LG, Vermes I. Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? Crit Care 6: 434–438, 2002.
    Crossref | PubMed | Web of Science | Google Scholar
  • 5. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117: 4003–4008, 2007.
    PubMed | Web of Science | Google Scholar
  • 6. Bhattacharyya N, Wiench M, Dumitrescu C, Connolly BM, Bugge TH, Patel HV, Gafni RI, Cherman N, Cho M, Hager GL, Collins MT. Mechanism of FGF23 processing in fibrous dysplasia. J Bone Miner Res 27: 1132–1141, 2012.
    Crossref | PubMed | Web of Science | Google Scholar
  • 7. Bolton CH, Downs LG, Victory JG, Dwight JF, Tomson CR, Mackness MI, Pinkney JH. Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines. Nephrol Dial Transplan 16: 1189–1197, 2001.
    Crossref | PubMed | Web of Science | Google Scholar
  • 8. Cheng SP, Liu CL, Liu TP, Hsu YC, Lee JJ. Association between parathyroid hormone levels and inflammatory markers among US adults. Mediat Inflamm 2014: 709024, 2014.
    Crossref | PubMed | Web of Science | Google Scholar
  • 9. Clinkenbeard E, Stayrook K, Appaiah H, Cass T, Farrow E, Ivan M, Chan R, Schipani E, Clemens T, White KE. Erythropoietin and FGF23 cross-talk during iron-deficiency anemia. J Bone Miner Res 30, Suppl 1: 2015.
    Google Scholar
  • 10. Clinkenbeard EL, Farrow EG, Summers LJ, Cass TA, Roberts JL, Bayt CA, Lahm T, Albrecht M, Allen MR, Peacock M, White KE. Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice. J Bone Miner Res 29: 361–369, 2014.
    Crossref | PubMed | Web of Science | Google Scholar
  • 11. Coe LM, Madathil SV, Casu C, Lanske B, Rivella S, Sitara D. FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis. J Biol Chem 289: 9795–9810, 2014.
    Crossref | PubMed | Web of Science | Google Scholar
  • 12. Cooper MS, Bujalska I, Rabbitt E, Walker EA, Bland R, Sheppard MC, Hewison M, Stewart PM. Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res 16: 1037–1044, 2001.
    Crossref | PubMed | Web of Science | Google Scholar
  • 13. Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J, Taylor CT. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 103: 18154–18159, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 14. Dai B, David V, Martin A, Huang J, Li H, Jiao Y, Gu W, Quarles LD. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PloS One 7: e44161, 2012.
    Crossref | PubMed | Web of Science | Google Scholar
  • 15. David V, Dai B, Martin A, Huang J, Han X, Quarles LD. Calcium regulates FGF-23 expression in bone. Endocrinology 154: 4469–4482, 2013.
    Crossref | PubMed | Web of Science | Google Scholar
  • 16. David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89: 135–146, 2016.
    Crossref | PubMed | Web of Science | Google Scholar
  • 17. David V, Quarles LD. FGF23/Klotho new regulators of vitamin D metabolism. In: Vitamin D (3rd ed.), edited by Adams DFWPS. San Diego, CA: Academic, 2011, chapt. 42, p. 747–761.
    Crossref | Google Scholar
  • 18. Descamps-Latscha B, Herbelin A, Nguyen AT, Roux-Lombard P, Zingraff J, Moynot A, Verger C, Dahmane D, de Groote D, Jungers P. Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis Relationships with activation markers of T cells, B cells, and monocytes. J Immunol 154: 882–892, 1995.
    PubMed | Web of Science | Google Scholar
  • 19. Dewhirst FE, Stashenko PP, Mole JE, Tsurumachi T. Purification and partial sequence of human osteoclast-activating fa ctor: identity with interleukin 1 beta. J Immunol 135: 2562–2568, 1985.
    PubMed | Web of Science | Google Scholar
  • 20. Dounousi E, Torino C, Pizzini P, Cutrupi S, Panuccio V, D'Arrigo G, Abd ElHafeez S, Tripepi G, Mallamaci F, Zoccali C. Intact FGF23 and alphaklotho during acute inflammation/sepsis in CKD patients. Eur J Clin Invest 46: 234–241, 2016.
    Crossref | PubMed | Web of Science | Google Scholar
  • 21. El-Hodhod MA, Hamdy AM, Abbas AA, Moftah SG, Ramadan AA. Fibroblast growth factor 23 contributes to diminished bone mineral density in childhood inflammatory bowel disease. BMC Gastroenterol 12: 44, 2012.
    Crossref | PubMed | Web of Science | Google Scholar
  • 22. Elderman JH, Wabbijn M, de Jongh F. Hypophosphataemia due to FGF-23 producing B cell non-Hodgkin's lymphoma. Br Med J 2016: 2016.
    Google Scholar
  • 23. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med 364: 656–665, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 24. Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, Robling AG, Stayrook KR, Jideonwo V, Magers MJ, Garringer HJ, Vidal R, Chan RJ, Goodwin CB, Hui SL, Peacock M, White KE. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci USA 108: E1146–E1155, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 25. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St. John Sutton M., Ojo A., Gadegbeku C., Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro OM, Kusek JW, Keane MG, Wolf M. FGF23 induces left ventricular hypertrophy. J Clin Invest 121: 4393–4408, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 26. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, Ritz E, Kronenberg F, Kuen E, Konig P, Kraatz G, Mann JF, Muller GA, Kohler H, Riegler P. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 18: 2600–2608, 2007.
    Crossref | PubMed | Web of Science | Google Scholar
  • 27. Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, Li J, Shehadeh LA, Hare JM, David V, Martin A, Fornoni A, Di Marco GS, Kentrup D, Reuter S, Mayer AB, Pavenstadt H, Stypmann J, Kuhn C, Hille S, Frey N, Leifheit-Nestler M, Richter B, Haffner D, Abraham R, Bange J, Sperl B, Ullrich A, Brand M, Wolf M, Faul C. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab 22: 1020–1032, 2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • 28. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16: 2205–2215, 2005.
    Crossref | PubMed | Web of Science | Google Scholar
  • 29. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359: 584–592, 2008.
    Crossref | PubMed | Web of Science | Google Scholar
  • 30. Han X, Li L, Yang J, King G, Xiao Z, Quarles LD. Counter-regulatory paracrine actions of FGF-23 and 1,25(OH)2 D in macrophages. FEBS Lett 590: 53–67, 2016.
    Crossref | PubMed | Web of Science | Google Scholar
  • 31. Han X, Xiao Z, Quarles LD. Membrane and integrative nuclear fibroblastic growth factor receptor (FGFR) regulation of FGF-23. J Biol Chem 290: 10447–10459, 2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • 32. Hanks LJ, Casazza K, Judd SE, Jenny NS, Gutierrez OM. Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults. PloS One 10: e0122885, 2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • 33. Herbelin A, Urena P, Nguyen AT, Zingraff J, Descamps-Latscha B. Elevated circulating levels of interleukin-6 in patients with chronic renal failure. Kidney Int 39: 954–960, 1991.
    Crossref | PubMed | Web of Science | Google Scholar
  • 34. Holecki M, Chudek J, Owczarek A, Olszanecka-Glinianowicz M, Bozentowicz-Wikarek M, Dulawa J, Mossakowska M, Zdrojewski T, Skalska A, Wiecek A. Inflammation but not obesity or insulin resistance is associated with increased plasma fibroblast growth factor 23 concentration in the elderly. Clin Endocrinol 82: 900–909, 2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • 35. Iliopoulos D, Malizos KN, Oikonomou P, Tsezou A. Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PloS One 3: e3740, 2008.
    Crossref | PubMed | Web of Science | Google Scholar
  • 36. Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab 96: 3541–3549, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 37. Isakova T, Houston J, Santacruz L, Schiavenato E, Somarriba G, Harmon WG, Lipshultz SE, Miller TL, Rusconi PG. Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure. Pediatr Nephrol 28: 2035–2042, 2013.
    Crossref | PubMed | Web of Science | Google Scholar
  • 38. Isakova T, Wahl P, Vargas GS, Gutierrez OM, Scialla J, Xie H, Appleby D, Nessel L, Bellovich K, Chen J, Hamm L, Gadegbeku C, Horwitz E, Townsend RR, Anderson CA, Lash JP, Hsu CY, Leonard MB, Wolf M. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 79: 1370–1378, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 39. Ito N, Wijenayaka AR, Prideaux M, Kogawa M, Ormsby RT, Evdokiou A, Bonewald LF, Findlay DM, Atkins GJ. Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol Cell Endocrinol 399: 208–218, 2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • 40. Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 281: 18370–18377, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 41. Kitaoka T, Namba N, Miura K, Kubota T, Ohata Y, Fujiwara M, Hirai H, Yamamoto T, Ozono K. Decrease in serum FGF23 levels after intravenous infusion of pamidronate in patients with osteogenesis imperfecta. J Bone Miner Metab 29: 598–605, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 42. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191: 275–286, 2000.
    Crossref | PubMed | Web of Science | Google Scholar
  • 43. Kovesdy CP, Quarles LD. The role of fibroblast growth factor-23 in cardiorenal syndrome. Nephron Clin Pract 123: 194–201, 2013.
    Crossref | PubMed | Google Scholar
  • 44. Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, Westin G, Larsson TE. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195: 125–131, 2007.
    Crossref | PubMed | Web of Science | Google Scholar
  • 45. Kuhlicke J, Frick JS, Morote-Garcia JC, Rosenberger P, Eltzschig HK. Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PloS One 2: e1364, 2007.
    Crossref | PubMed | Web of Science | Google Scholar
  • 46. Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 299: F882–F889, 2010.
    Link | Web of Science | Google Scholar
  • 47. Lestz RM, Fivush BA, Atkinson MA. Association of higher erythropoiesis stimulating agent dose and mortality in children on dialysis. Pediatr Nephrol 29: 2021–2028, 2014.
    Crossref | PubMed | Web of Science | Google Scholar
  • 48. Li B, Baylink DJ, Deb C, Zannetti C, Rajaallah F, Xing W, Walter MH, Lau KH, Qin X. 1,25-Dihydroxyvitamin D3 suppresses TLR8 expression and TLR8-mediated inflammatory responses in monocytes in vitro and experimental autoimmune encephalomyelitis in vivo. PloS One 8: e58808, 2013.
    Crossref | PubMed | Web of Science | Google Scholar
  • 49. Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 278: 37419–37426, 2003.
    Crossref | PubMed | Web of Science | Google Scholar
  • 50. Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17: 1305–1315, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 51. Malyszko J, Mysliwiec M. Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Pressure Res 30: 15–30, 2007.
    Crossref | PubMed | Web of Science | Google Scholar
  • 52. Manghat P, Fraser WD, Wierzbicki AS, Fogelman I, Goldsmith DJ, Hampson G. Fibroblast growth factor-23 is associated with C-reactive protein, serum phosphate and bone mineral density in chronic kidney disease. Osteoporosis Int 21: 1853–1861, 2010.
    Crossref | PubMed | Web of Science | Google Scholar
  • 53. Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev 92: 131–155, 2012.
    Link | Web of Science | Google Scholar
  • 54. Masi L, Cavalli L, Falcini F, Franceschelli F, Leoncini G, Fossi C, Brandi ML. P8-Measurement of fibroblast growth factor-23 (FGF23) in the serum of patients affected by juvenile systemic lupus erythematosus: a possible marker of kidney damage. Clin Case Miner Bone Metab 7: 214–214, 2010.
    Google Scholar
  • 55. Masuda Y, Ohta H, Morita Y, Nakayama Y, Miyake A, Itoh N, Konishi M. Expression of Fgf23 in activated dendritic cells and macrophages in response to immunological stimuli in mice. Biol Pharm Bull 38: 687–693, 2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • 56. Morvan F, Boulukos K, Clement-Lacroix P, Roman Roman S, Suc-Royer I, Vayssiere B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21: 934–945, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 57. Munoz Mendoza J, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH, Bazzano LA, Xie D, Kretzler M, Nessel L, Hamm LL, Negrea L, Leonard MB, Raj D, Wolf M, Chronic Renal Insufficiency Cohort. Fibroblast growth factor 23 and Inflammation in CKD. Clin J Am Soc Nephrol 7: 1155–1162, 2012.
    Crossref | PubMed | Web of Science | Google Scholar
  • 58. Nakatani T, Sarraj B, Ohnishi M, Densmore MJ, Taguchi T, Goetz R, Mohammadi M, Lanske B, Razzaque MS. In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis. FASEB J 23: 433–441, 2009.
    Crossref | PubMed | Web of Science | Google Scholar
  • 59. Naqvi SB, Collins AJ. Infectious complications in chronic kidney disease. Advan Chronic Kidney Dis 13: 199–204, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 60. Navarro-Gonzalez JF, Mora-Fernandez C, Muros M, Herrera H, Garcia J. Mineral metabolism and inflammation in chronic kidney disease patients: a cross-sectional study. Clin J Am Soc Nephrol 4: 1646–1654, 2009.
    Crossref | PubMed | Web of Science | Google Scholar
  • 61. Oelzner P, Muller A, Deschner F, Huller M, Abendroth K, Hein G, Stein G. Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif Tissue Int 62: 193–198, 1998.
    Crossref | PubMed | Web of Science | Google Scholar
  • 62. Olauson H, Lindberg K, Amin R, Sato T, Jia T, Goetz R, Mohammadi M, Andersson G, Lanske B, Larsson TE. Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 9: e1003975, 2013.
    Crossref | PubMed | Web of Science | Google Scholar
  • 63. Prie D, Forand A, Francoz C, Elie C, Cohen I, Courbebaisse M, Eladari D, Lebrec D, Durand F, Friedlander G. Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list. PloS One 8: e66182, 2013.
    Crossref | PubMed | Web of Science | Google Scholar
  • 64. Puts MT, Visser M, Twisk JW, Deeg DJ, Lips P. Endocrine and inflammatory markers as predictors of frailty. Clin Endocrinol 63: 403–411, 2005.
    Crossref | PubMed | Web of Science | Google Scholar
  • 65. Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118: 3820–3828, 2008.
    Crossref | PubMed | Web of Science | Google Scholar
  • 66. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453: 807–811, 2008.
    Crossref | PubMed | Web of Science | Google Scholar
  • 67. Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 66: 5314–5321, 1998.
    PubMed | Web of Science | Google Scholar
  • 68. Rossaint J, Oehmichen J, Van Aken H, Reuter S, Pavenstadt HJ, Meersch M, Unruh M, Zarbock A. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest 126: 962–974, 2016.
    Crossref | PubMed | Web of Science | Google Scholar
  • 69. Sainaghi PP, Bellan M, Antonini G, Bellomo G, Pirisi M. Unsuppressed parathyroid hormone in patients with autoimmune/inflammatory rheumatic diseases: implications for vitamin D supplementation. Rheumatology 50: 2290–2296, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 70. Sato H, James Kazama J, Murasawa A, Otani H, Abe A, Ito S, Ishikawa H, Nakazono K, Kuroda T, Nakano M, Narita I. Serum fibroblast growth factor 23 (FGF23) in patients with rheumatoid arthritis. Int Med 55: 121–126, 2016.
    Crossref | PubMed | Web of Science | Google Scholar
  • 71. Schett G, Kiechl S, Weger S, Pederiva A, Mayr A, Petrangeli M, Oberhollenzer F, Lorenzini R, Redlich K, Axmann R, Zwerina J, Willeit J. High-sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study. Arch Intern Med 166: 2495–2501, 2006.
    Crossref | PubMed | Google Scholar
  • 72. Schwartz A, Brotfain E, Koyfman L, Kutz R, Gruenbaum SE, Klein M, Zlotnik A. Association between hypophosphatemia and cardiac arrhythmias in the early stage of sepsis: could phosphorus replacement treatment reduce the incidence of arrhythmias? Electrolyte Blood Pressure 12: 19–25, 2014.
    Crossref | PubMed | Google Scholar
  • 73. Schwartz A, Gurman G, Cohen G, Gilutz H, Brill S, Schily M, Gurevitch B, Shoenfeld Y. Association between hypophosphatemia and cardiac arrhythmias in the early stages of sepsis. Eur J Intern Med 13: 434, 2002.
    Crossref | PubMed | Google Scholar
  • 74. Shankar A, Sun L, Klein BE, Lee KE, Muntner P, Nieto FJ, Tsai MY, Cruickshanks KJ, Schubert CR, Brazy PC, Coresh J, Klein R. Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study. Kidney Int 80: 1231–1238, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 75. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113: 561–568, 2004.
    Crossref | PubMed | Web of Science | Google Scholar
  • 76. Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, Czaja MJ, Bartz R, Abraham R, Di Marco GS, Brand M, Wolf M, Faul C. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int In press.
    Google Scholar
  • 77. Sommer A, Fabri M. Vitamin D regulates cytokine patterns secreted by dendritic cells to promote differentiation of IL-22-producing T cells. PloS One 10: e0130395, 2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • 78. Stenvinkel P. Endothelial dysfunction and inflammation-is there a link? Nephrol Dial Transplan 16: 1968–1971, 2001.
    Crossref | PubMed | Web of Science | Google Scholar
  • 79. Stenvinkel P. Inflammatory and atherosclerotic interactions in the depleted uremic patient. Blood Pur 19: 53–61, 2001.
    Crossref | PubMed | Web of Science | Google Scholar
  • 80. Stenvinkel P. Interactions between inflammation, oxidative stress, and endothelial dysfunction in end-stage renal disease. J Renal Nutr 13: 144–148, 2003.
    Crossref | PubMed | Web of Science | Google Scholar
  • 81. Stewart I, Roddie C, Gill A, Clarkson A, Mirams M, Coyle L, Ward C, Clifton-Bligh P, Robinson BG, Mason RS, Clifton-Bligh RJ. Elevated serum FGF23 concentrations in plasma cell dyscrasias. Bone 39: 369–376, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 82. Streja E, Park J, Chan TY, Lee J, Soohoo M, Rhee CM, Arah OA, Kalantar-Zadeh K. Erythropoietin dose and mortality in hemodialysis patients: marginal structural model to examine causality. Int J Nephrol 2016: 6087134, 2016.
    Crossref | PubMed | Web of Science | Google Scholar
  • 83. Stubbs JR, Liu S, Tang W, Zhou J, Wang Y, Yao X, Quarles LD. Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 18: 2116–2124, 2007.
    Crossref | PubMed | Web of Science | Google Scholar
  • 84. Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh AK. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 74: 791–798, 2008.
    Crossref | PubMed | Web of Science | Google Scholar
  • 85. Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, Koller A, Nizet V, White KE, Dixon JE. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci USA 111: 5520–5525, 2014.
    Crossref | PubMed | Web of Science | Google Scholar
  • 86. Thomson BM, Mundy GR, Chambers TJ. Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol 138: 775–779, 1987.
    PubMed | Web of Science | Google Scholar
  • 87. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349: 2483–2494, 2003.
    Crossref | PubMed | Web of Science | Google Scholar
  • 88. Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36: 579–581, 2004.
    Crossref | PubMed | Web of Science | Google Scholar
  • 89. Touchberry CD, Green TM, Tchikrizov V, Mannix JE, Mao TF, Carney BW, Girgis M, Vincent RJ, Wetmore LA, Dawn B, Bonewald LF, Stubbs JR, Wacker MJ. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab 304: E863–E873, 2013.
    Link | Web of Science | Google Scholar
  • 90. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770–774, 2006.
    Crossref | PubMed | Web of Science | Google Scholar
  • 91. Viaene L, Evenepoel P, Meijers B, Vanderschueren D, Overbergh L, Mathieu C. Uremia suppresses immune signal-induced CYP27B1 expression in human monocytes. Am J Nephrol 36: 497–508, 2012.
    Crossref | PubMed | Web of Science | Google Scholar
  • 92. Wang CY, Babitt JL. Hepcidin regulation in the anemia of inflammation. Curr Opin Hematol 23: 189–197, 2016.
    Crossref | PubMed | Web of Science | Google Scholar
  • 93. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173: 2909–2912, 2004.
    Crossref | PubMed | Web of Science | Google Scholar
  • 94. Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta 1790: 682–693, 2009.
    Crossref | PubMed | Web of Science | Google Scholar
  • 95. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 352: 1011–1023, 2005.
    Crossref | PubMed | Web of Science | Google Scholar
  • 96. Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res 28: 1793–1803, 2013.
    Crossref | PubMed | Web of Science | Google Scholar
  • 97. Wolf M, Molnar MZ, Amaral AP, Czira ME, Rudas A, Ujszaszi A, Kiss I, Rosivall L, Kosa J, Lakatos P, Kovesdy CP, Mucsi I. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol 22: 956–966, 2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 98. Wolf M, White KE. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens 23: 411–419, 2014.
    Crossref | PubMed | Web of Science | Google Scholar
  • 99. Yamada S, Tokumoto M, Tatsumoto N, Taniguchi M, Noguchi H, Nakano T, Masutani K, Ooboshi H, Tsuruya K, Kitazono T. Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia. Am J Physiol Renal Physiol 306: F1418–F1428, 2014.
    Link | Web of Science | Google Scholar
  • 100. Yamazaki M, Kawai M, Miyagawa K, Ohata Y, Tachikawa K, Kinoshita S, Nishino J, Ozono K, Michigami T. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation. J Bone Miner Metab 33: 342–354, 2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • 101. Yan L, Bowman MA. Chronic sustained inflammation links to left ventricular hypertrophy and aortic valve sclerosis: a new link between S100/RAGE and FGF23. Inflamm Cell Signal 1: 2014.
    PubMed | Google Scholar
  • 102. Yu X, Ibrahimi OA, Goetz R, Zhang F, Davis SI, Garringer HJ, Linhardt RJ, Ornitz DM, Mohammadi M, White KE. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology 146: 4647–4656, 2005.
    Crossref | PubMed | Web of Science | Google Scholar

AUTHOR NOTES

  • Address for reprint requests and other correspondence: J. L. Babitt, Massachusetts General Hospital, 185 Cambridge St., CPZN-8208, Boston, MA 02114 (e-mail: ).
Download PDF
Back to Top
Next