FGF23: Bone-Derived Phosphatonin Regulating Renal Phosphate and Vitamin D with Cardiovascular Effects via α-Klotho in Research

# FGF23: Bone-Derived Phosphatonin Regulating Renal Phosphate and Vitamin D with Cardiovascular Effects via α-Klotho in Research

Fibroblast growth factor 23 (FGF23) is a member of the FGF19 subfamily of endocrine FGFs that functions as a bone-derived phosphatonin — a hormone that reduces blood phosphate levels by acting on the kidney to suppress phosphate reabsorption and vitamin D activation. Identified in the early 2000s through the study of genetic phosphate-wasting disorders, FGF23 has emerged as one of the most clinically significant bone-derived hormones, playing central roles in mineral homeostasis, CKD pathophysiology, and cardiovascular disease. Its tight functional coupling with α-klotho (the anti-aging protein that serves as its co-receptor) has made the FGF23-klotho axis a major focus of CKD, aging, and cardiovascular research. The development of burosumab (anti-FGF23 monoclonal antibody) and its FDA approval for X-linked hypophosphatemia represented a landmark treatment for a previously refractory bone disease.

Discovery Through Genetic Phosphate-Wasting Disorders

FGF23 was identified in 2000-2001 through the genetic study of tumor-induced osteomalacia (TIO) and autosomal dominant hypophosphatemic rickets (ADHR):

ADHR discovery: White et al. (2000,) performed positional cloning in a large kindred with ADHR — a phosphate-wasting bone disease with hypophosphatemia, inappropriately low 1,25(OH)₂D₃, and rickets/osteomalacia — and identified missense mutations in FGF23 (R176Q, R179Q, R179W). These mutations were in the consensus site for proprotein convertase (furin) cleavage of FGF23, preventing its proteolytic inactivation and causing FGF23 accumulation.

TIO/tumor-expressed FGF23: Tumor-induced osteomalacia is a paraneoplastic syndrome where phosphaturic mesenchymal tumors secrete excess phosphatonins causing severe hypophosphatemia. Shimada et al. (2001, PMID: 11717385) identified FGF23 as the TIO-secreted phosphatonin by purifying the factor from tumor extracts and confirming its hypophosphatemic activity.

X-linked hypophosphatemia (XLH): XLH, caused by loss-of-function mutations in PHEX (phosphate-regulating endopeptidase homolog, X-linked), shows massively elevated FGF23. PHEX normally inactivates FGF23, so PHEX loss → FGF23 accumulation → hypophosphatemia. This disease model led directly to the therapeutic hypothesis that anti-FGF23 antibody would treat XLH.

Gene and Protein Structure

FGF23 Gene

The human FGF23 gene is located on chromosome 12p13.3 and encodes a 251-amino acid precursor. After signal peptide cleavage, the 227-amino acid mature protein (molecular weight ~32 kDa, ~37 kDa with glycosylation) has:

• •An N-terminal FGF homology domain: contains the FGFR-binding surface (residues 25-179 approximately)
• •A C-terminal tail (residues 180-251): unique to FGF23, contains the 176-RXXR-179 furin cleavage site; the intact C-terminal tail is required for klotho binding
• •O-glycosylation at Thr178 by GALNT3 (GalNAc transferase 3): critical — O-glycosylation of T178 prevents furin cleavage, stabilizing intact FGF23; mutations in GALNT3 cause familial tumoral calcinosis (FTC) through FGF23 degradation

Proteolytic processing: Furin and other subtilisin-like proprotein convertases cleave FGF23 at RHTR176/ADYNL (the 176RXXR179 site) into:

• •N-terminal fragment (residues 25-179, ~15 kDa): can bind FGFRs but does not bind klotho → biologically inactive or antagonistic
• •C-terminal fragment (residues 180-251, ~12 kDa): cannot bind FGFRs → biologically inactive

Only intact FGF23 (both N and C domains intact, with O-glycosylated T178) is biologically active. The ratio of intact FGF23 to degradation fragments determines net biological activity — understanding the forms present in CKD plasma is an important assay consideration.

Receptor System: FGFR1/4 + α-Klotho Co-Receptor

FGF23 signals through a unique high-affinity ternary complex:

1. FGFR1c (primary in kidney): Low-affinity FGF23 binding when alone

2. α-Klotho (KL): Type I single-pass membrane protein expressed in kidney distal tubule, parathyroid gland, and choroid plexus; forms a stable complex with FGFR1c that dramatically increases FGF23 binding affinity (~Kd 10-100 pM vs. >1 nM without klotho)

3. The ternary complex (FGF23-FGFR1c-KL): Signals through FGFR tyrosine kinase → Ras-MAPK (ERK1/2) pathway → transcriptional regulation

FGFR4: In cardiomyocytes and hepatocytes, FGF23 signals through FGFR4 in a klotho-independent manner (cardiomyocytes have minimal klotho). This klotho-independent FGFR4 signaling is responsible for FGF23's cardiac effects (left ventricular hypertrophy) and hepatic effects (reduced 25-hydroxyvitamin D synthesis).

Soluble klotho (sKL): Ectodomain shedding of membrane klotho by ADAM10/17 releases soluble klotho into circulation. Soluble klotho (~130 kDa) can act as a coreceptor for FGF23 in tissues that lack membrane klotho, expanding FGF23's target range. Soluble klotho also has FGF23-independent cytoprotective effects on endothelium, kidney, and cardiac tissue.

Physiological Functions in Mineral Metabolism

Phosphate Regulation

FGF23 is the master regulator of phosphate homeostasis:

1. Proximal tubule: FGF23-FGFR1-KL complex activates ERK1/2 → phosphorylation and internalization of NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) sodium-phosphate cotransporters from the brush border → reduced phosphate reabsorption → phosphaturia

2. Suppression of 1,25-dihydroxyvitamin D synthesis: FGF23 reduces CYP27B1 (1α-hydroxylase) expression in proximal tubule cells → less conversion of 25-OH-D₃ to 1,25(OH)₂D₃ (the active form)

3. Increased 1,25-dihydroxyvitamin D degradation: FGF23 increases CYP24A1 (24-hydroxylase) expression → faster degradation of 1,25(OH)₂D₃

4. Suppression of parathyroid hormone (PTH): In parathyroid gland (which expresses both FGFR1 and KL), FGF23 directly suppresses PTH synthesis and secretion. This PTH suppression is lost in CKD (when klotho is reduced), contributing to secondary hyperparathyroidism.

The result: FGF23 reduces serum phosphate, reduces 1,25(OH)₂D₃, and suppresses PTH — a phosphate-lowering regulatory axis that is the primary check against hyperphosphatemia after dietary phosphate absorption.

What Stimulates FGF23 Production?

Osteocytes and osteoblasts regulate FGF23 production in response to:

• •Dietary phosphate: High phosphate intake → FGF23 increases
• •1,25(OH)₂D₃: Active vitamin D is the most potent inducer of FGF23 transcription (via VDR binding to FGF23 promoter) — a negative feedback
• •PTH: PTH stimulates FGF23 via cAMP/PKA in osteoblasts/osteocytes
• •Iron deficiency: Inhibits GALNT3-mediated O-glycosylation → more furin cleavage → less intact FGF23 (note: in ADHR, iron deficiency causes disease flares because ADHR mutations prevent furin cleavage, so iron deficiency raises FGF23 further)
• •Inflammation (IL-6, TNF-α): Directly induce FGF23 in osteoblasts

Reciprocal Regulation: FGF23-PTH-Vitamin D Axis

FGF23, PTH, and 1,25(OH)₂D₃ form an integrated regulatory triad:

• •Phosphate↑ → FGF23↑ → PTH↓, 1,25-D↓
• •PTH↑ (from hypocalcemia or independent) → FGF23↑
• •1,25-D↑ → FGF23↑ (negative feedback)
• •FGF23↑ → 1,25-D↓ → PTH↑ (secondary hyperparathyroidism when FGF23 is chronically elevated, and klotho is depleted in CKD)

FGF23 in Chronic Kidney Disease

The CKD-FGF23-Cardiovascular Death Axis

FGF23 is among the most important biomarkers and pathogenic mediators discovered in CKD research over the past two decades:

Progressive FGF23 elevation in CKD: As GFR declines, phosphate clearance is reduced, stimulating FGF23 to maintain phosphate homeostasis. FGF23 rises progressively from CKD stage 1 (barely above normal) through stage 5/ESRD (1,000-10,000 times normal). This rise precedes detectable hyperphosphatemia by years.

FGF23 as CKD biomarker: Serum FGF23 is among the earliest markers of CKD-mineral-bone disorder (CKD-MBD), rising before PTH or phosphate become abnormal. Elevated FGF23 independently predicts:

• •CKD progression (Isakova et al., 2011,)
• •All-cause and cardiovascular mortality in CKD and ESRD
• •Incident CKD in general population cohorts

FGF23-driven left ventricular hypertrophy (LVH): Faul et al. (2011,) demonstrated that excess FGF23 directly causes LVH through klotho-independent FGFR4 signaling in cardiomyocytes. This finding was revolutionary: CKD patients die predominantly of cardiovascular disease, and elevated FGF23 (via FGFR4→calcineurin-NFAT→cardiomyocyte hypertrophy) mechanistically explains why. Anti-FGFR4 antibody treatment in rodent CKD models prevented FGF23-induced LVH without affecting phosphate metabolism.

The klotho deficiency amplification: In CKD, reduced kidney mass → reduced klotho expression → less FGF23 signaling efficiency in the remaining kidney → compensatory FGF23 rise. Additionally, klotho deficiency removes the protective cardiac effects of soluble klotho, compounding cardiovascular risk.

X-Linked Hypophosphatemia (XLH) and Burosumab

XLH (OMIM #307800) is the most common hereditary rickets, affecting ~1:20,000 individuals, caused by hemizygous loss-of-function mutations in PHEX. PHEX normally activates matrix proteins that stabilize FGF23 protein in bone, so PHEX loss → FGF23 accumulation → phosphaturia → hypophosphatemia → rickets/osteomalacia. Traditional treatment with oral phosphate + vitamin D analogs was burdensome and incompletely effective.

Burosumab (Crysvita, Ultragenyx/Kyowa Kirin): A fully human monoclonal antibody against intact FGF23, burosumab neutralizes circulating FGF23, increasing renal phosphate reabsorption and normalizing 1,25(OH)₂D₃ synthesis.

Phase 3 trials: Imel et al. (2019) and associated trials demonstrated that burosumab in XLH pediatric patients:

• •Normalized serum phosphate in >85% of patients
• •Significantly improved rickets severity scores (RSS)
• •Improved walking distance and growth
• •Reduced alkaline phosphatase

FDA and EMA approval: Burosumab received FDA approval in April 2018 for XLH in adults and in June 2018 for pediatric XLH (≥1 year), and subsequently for tumor-induced osteomalacia. It is the first anti-FGF23 antibody approved for clinical use and represents a paradigm shift from symptom management to molecular correction of the FGF23 excess.

CKD applications: The use of anti-FGF23 strategies in CKD-MBD is more complex, given that FGF23 elevation in CKD is an adaptation; simply blocking it risks hyperphosphatemia. Clinical trials of FGF23-targeted strategies in CKD continue, with attention to the trade-off between cardiac protection and mineral homeostasis.

Hereditary Tumoral Calcinosis: The Opposite of XLH

If XLH represents FGF23 excess (hypophosphatemia), familial tumoral calcinosis (FTC) represents FGF23 deficiency:

• •FTC caused by mutations in FGF23 itself (gain-of-function furin cleavage), GALNT3, or KL
• •Results in hyperphosphatemia, elevated 1,25(OH)₂D₃, and massive ectopic calcifications
• •Rare but provides definitive genetic evidence for FGF23's physiological roles

Research Tools and Experimental Systems

Current Research Frontiers

FGF23 as CKD cardiovascular risk modifier: Clinical trials testing whether phosphate binders, dietary phosphate restriction, or moderate FGF23 reduction reduce cardiovascular events in CKD patients are ongoing. The CARDINAL trial evaluated ferric citrate (reduces phosphate absorption) on FGF23 in CKD.

Anti-FGFR4 for CKD-LVH: Since FGFR4-mediated LVH is klotho-independent, anti-FGFR4 antibodies or FGFR4-selective kinase inhibitors could protect the CKD heart without affecting renal phosphate handling. Several selective FGFR4 inhibitors have been developed for cancer indications and may be repurposed for CKD cardiac protection.

Soluble klotho supplementation: Declining soluble klotho in CKD and aging is proposed as an anti-aging and cardioprotective target. Recombinant soluble klotho infusion in CKD rodent models reduces FGF23 resistance, protects cardiac and renal function. Clinical development of soluble klotho is in early phases.

FGF23 in non-CKD contexts: FGF23 is elevated in heart failure (independent of CKD), and elevated FGF23 predicts adverse outcomes in HFpEF. Whether FGF23 is a biomarker or mediator of HF progression (via FGFR4/cardiac fibrosis mechanisms) is being investigated.

Iron deficiency and FGF23: Iron deficiency in XLH causes disease flares by impairing O-glycosylation and increasing FGF23 cleavage (paradoxically, less intact FGF23 in general; but in ADHR, iron deficiency raises intact FGF23). Iron repletion is part of XLH management and affects FGF23 metabolism.

Conclusion

FGF23 was established as the missing link between bone, kidney, and mineral homeostasis through the elegant genetic logic of hypophosphatemic rickets and tumor-induced osteomalacia research. Its functional coupling with α-klotho as a co-receptor explains why klotho-deficient states (CKD, aging) amplify FGF23's pathological effects while losing beneficial signaling specificity. The discovery of FGFR4-mediated LVH as a FGF23 target independent of klotho provided a mechanistic explanation for the excess cardiovascular mortality in CKD that has driven multiple therapeutic trials. Burosumab's FDA approval for XLH validated anti-FGF23 therapy as clinically feasible and effective, and established a precedent for targeting bone-derived hormones in genetic mineral disorders. The FGF23-klotho-vitamin D-PTH regulatory axis is now recognized as one of the most complex and clinically consequential mineral homeostasis networks in human physiology. Intact FGF23 ELISAs, recombinant FGF23 protein, and the Hyp mouse model are the primary research tools; burosumab is available as both a clinical agent and a research pharmacological probe.

Key References

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 USA. 2001;98(11):6500-6505. PMID: 11344269

3. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770-774. PMID: 17086194

4. Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in CKD. Kidney Int. 2011;79(12):1370-1378. PMID: 21389978

5. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393-4408. PMID: 21985787

6. Imel EA, Zhang X, DiMeglio LA, et al. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. J Clin Endocrinol Metab. 2015;100(7):2565-2573. PMID: 25880098

7. 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(3):429-435. PMID: 15040831

8. Goetz R, Beenken A, Ibrahimi OA, et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol. 2007;27(9):3417-3428. PMID: 17339340

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This article is intended for Research Use Only (RUO). The information provided describes laboratory research findings and does not constitute medical advice. Burosumab (anti-FGF23) is an FDA-approved medication for specific indications. All other FGF23-related research applications must comply with applicable institutional, local, and national regulations.