FGF23 Human

What is FGF23 and what is its primary physiological function?

FGF23 is a hormone primarily secreted by osteocytes and osteoblasts in bone tissue. Its main physiological role is maintaining mineral ion homeostasis, particularly phosphate and vitamin D metabolism. FGF23 acts on the kidneys to decrease phosphate reabsorption in the proximal tubule and inhibits 1α-hydroxylase, the enzyme that activates vitamin D. This coordinated action allows FGF23 to reduce serum phosphate levels while modulating vitamin D metabolism, creating a sophisticated control system for mineral homeostasis .

Which cell types produce FGF23 in humans?

While FGF23 was initially identified as being produced mainly by osteocytes and osteoblasts, research has uncovered additional sources:

• Bone-embedded osteocytes (primary source)

• Osteoblasts in bone tissue

• Erythroblasts (red blood cell precursors) in the bone marrow, triggered by hypoxic conditions

• In pathological states like autosomal dominant polycystic kidney disease (ADPKD), polycystic liver tissue has been shown to produce FGF23

What are the primary clinical conditions associated with altered FGF23 levels?

Several clinical conditions are associated with abnormal FGF23 levels:

• Chronic Kidney Disease (CKD): FGF23 rises early in CKD progression

• Hereditary hypophosphatemic rickets: Caused by autonomous FGF23 overproduction

• Tumor-induced osteomalacia: Results from ectopic FGF23 production by mesenchymal tumors

• Autosomal dominant polycystic kidney disease: Associated with elevated FGF23 even with preserved renal function

• Cardiovascular disease: Elevated FGF23 is an independent risk factor for cardiovascular events and mortality

• Obesity: Higher FGF23 levels observed particularly in men and postmenopausal women with abdominal obesity

What are the optimal specimen collection methods for FGF23 measurement?

Researchers should consider the following evidence-based recommendations for specimen collection:

• Specimen type: Plasma (using K2-EDTA anticoagulant) generally shows higher FGF23 levels than serum. Australian researchers demonstrated remarkably lower FGF23 levels in serum compared to plasma, and the addition of protease inhibitors did not enhance stability .

• Collection timing: For intact FGF23 (iFGF23), morning samples are preferable due to significant diurnal variation with peak values in the morning. C-terminal FGF23 (cFGF23) shows more modest changes throughout the day .

• Fasting status: While some studies suggest minimal impact of fasting on cFGF23, iFGF23 concentrations may increase after phosphate intake with a delay of at least 12 hours. For consistency in research protocols, fasting morning samples are generally preferable, especially for iFGF23 measurement .

How do different FGF23 assay types compare and when should each be used?

Two main types of FGF23 assays are available with distinct characteristics:

For research focused on clinical risk assessment or epidemiological studies, cFGF23 assays may be preferable due to better precision and stronger associations with outcomes. For mechanistic studies examining immediate biological effects, iFGF23 assays might provide more relevant information .

What are the precision and reproducibility challenges with FGF23 measurement?

Precision and reproducibility vary considerably among FGF23 assays:

• Manufacturer-stated precision is not always reproducible in clinical laboratories, making verification essential

• According to biological variation data, desirable precision for clinical assays should be lower than 7%

• Studies suggest cFGF23 assays show better analytical precision than iFGF23 assays

• Significant intraindividual variation has been reported, particularly in dialysis patients

• Published precision data for common assays:

  • Quidel-Immutopics iFGF23: intra-assay CV <4.1%, inter-assay CV <9.1%

  • Kainos iFGF23: intra-assay CV <3%, inter-assay CV <3.8%

  • Total CVs for clinical samples can significantly exceed manufacturer claims

How should researchers address standardization issues between different FGF23 assays?

Standardization challenges require specific approaches:

• No international standard for FGF23 exists, preventing true assay standardization

• Method comparisons show substantial differences between assays that vary by concentration range and patient population

• Examples:

  • Immutopics iFGF23 measures ~55% lower than Kainos in healthy subjects but 90% lower in hemodialysis patients

  • Millipore assay measures 15% lower than Kainos in healthy subjects but 50% lower in hemodialysis patients

  • Correlation coefficients between different iFGF23 assays are often poor

Recommendations:

• Use the same assay throughout a study

• Specify the exact assay used when reporting results

• Use assay-specific reference ranges

• Consider performing method comparison studies if comparing to published literature

• Be aware that conversion factors between assays may vary by population and concentration range

What is the role of FGF23 in hematopoietic stem cell mobilization?

A groundbreaking discovery by Kobe University researchers revealed a novel function of FGF23 in hematopoiesis:

• Erythroblasts in bone marrow produce FGF23 in response to hypoxic conditions

• This production is triggered by granulocyte colony-stimulating factor (G-CSF) administration

• High FGF23 concentration in bone marrow promotes hematopoietic stem cell mobilization into peripheral blood

• The mechanism involves suppression of chemokine receptors that normally retain these cells in bone marrow

• This discovery expands understanding of FGF23 beyond mineral metabolism and may contribute to developing new strategies for harvesting hematopoietic stem cells from bone marrow transplant donors

How does FGF23 interact with other hormones in mineral metabolism?

FGF23 functions within a complex regulatory network involving several hormones:

• Vitamin D: FGF23 suppresses 1α-hydroxylase and activates 24-hydroxylase, reducing active vitamin D; in turn, vitamin D stimulates FGF23 production, creating a feedback loop

• Parathyroid hormone (PTH): FGF23 can suppress PTH secretion while PTH stimulates FGF23 production in bone; in CKD, resistance to FGF23's effects on PTH may contribute to secondary hyperparathyroidism

• Aldosterone: Mineralocorticoids influence FGF23 transcription and release. Research in mice demonstrated that aldosterone upregulates FGF23 expression by affecting store-operated Ca²⁺ entry (SOCE)

• Klotho: FGF23 requires this co-receptor for many physiological effects; declining Klotho levels in CKD may lead to FGF23 resistance for phosphaturic effects

What is the biological variability of FGF23 and how does it impact experimental design?

Understanding FGF23's biological variability is crucial for research design:

• Diurnal variation:

  • iFGF23 shows considerable diurnal variation with peak values in the morning

  • cFGF23 shows more modest changes throughout the day

• Within-individual variation:

  • Week-to-week variation of cFGF23 has been reported in hemodialysis patients

  • Some studies suggest cFGF23 has lower within-individual variation than PTH in dialysis patients

• Between-individual variation:

  • cFGF23 shows higher between-individual than within-individual variation

Research implications:

• Standardize sample collection timing, preferably in the morning

• For longitudinal studies, maintain consistent timing

• Include appropriate power calculations accounting for within-individual variability

• For iFGF23 studies, consider using fasting morning samples

• Document and control for factors known to influence FGF23 levels (diet, medications)

How should researchers establish and use reference ranges for FGF23?

Reference ranges must be assay-specific and carefully established:

• Reference ranges vary significantly between assays due to lack of standardization

• For several commercial assays, reference values have been established in literature

• Gender and age do not appear to have major effects on reference ranges for most populations

• Dietary phosphate content should be considered when interpreting results

• Different patient populations (healthy individuals, CKD patients, dialysis patients) may require specific reference ranges

Recommendations:

• Use assay-specific reference ranges from manufacturers or literature

• Consider establishing study-specific reference ranges for your population

• Document the specific assay, specimen type, and population characteristics

• Be cautious when comparing values to reference ranges established using different assays

How do demographic and clinical factors affect FGF23 levels?

Multiple factors influence FGF23 levels that should be considered in research:

• Sex differences:

  • Higher FGF23 levels in obese men compared to women

  • Stronger association between FGF23 and fat mass in men

  • Postmenopausal women with abdominal obesity show higher FGF23 than premenopausal women

• Body composition:

  • Obesity, larger waist circumference, and higher fat mass correlate with increased FGF23

  • Abdominal obesity shows particularly strong associations

• Clinical conditions:

  • Chronic kidney disease: progressive elevation with declining renal function

  • ADPKD: elevated levels even with preserved renal function

  • Hyperaldosteronism: upregulates FGF23 expression

• Dietary factors:

  • Phosphate content of diet affects baseline FGF23 levels

  • Cultural dietary patterns may influence population reference ranges

How can researchers analyze the relationship between FGF23 and clinical outcomes?

Statistical approaches for FGF23 outcome studies should consider:

• Distribution characteristics:

  • FGF23 values often show skewed distribution, particularly in disease states

  • Log transformation may be necessary for parametric analyses

• Longitudinal analyses:

  • Account for within-individual variability

  • Consider time-of-day effects for repeated measurements

  • Mixed-effects models may be appropriate

• Correlation with outcomes:

  • Multivariate models should adjust for relevant confounders (renal function, vitamin D, PTH)

  • Consider non-linear relationships with outcomes

  • Examine potential interaction effects with other mineral metabolism parameters

• Survival analyses:

  • Cox proportional hazards models have established FGF23 as an independent mortality risk factor

  • C-terminal FGF23 has been more consistently associated with mortality risk in meta-analyses

What are the cardiovascular implications of elevated FGF23?

FGF23's role in cardiovascular pathophysiology is increasingly recognized:

• Elevated FGF23 is independently associated with mortality in hemodialysis patients

• C-terminal FGF23 is a better predictor of cardiovascular disease and heart failure than intact FGF23

• Meta-analyses show C-terminal FGF23 is significantly associated with all-cause mortality risk

• Potential mechanisms include:

  • Direct effects on cardiac tissue leading to left ventricular hypertrophy

  • Interactions with the renin-angiotensin-aldosterone system

  • Effects on vascular calcification

  • Partial mediation through obesity and dyslipidemia

What novel measurement approaches are being developed for FGF23?

While immunoassays remain the current standard, researchers are exploring new approaches:

• LC-MS/MS methods are being investigated to quantify both intact and fragmented FGF23

• These methods could help standardize measurements and provide better understanding of fragment biology

• Improved standardization would address current limitations in comparing results across studies

• Novel assays may help determine whether C-terminal fragments have distinct biological activities that counteract the phosphaturic action of intact FGF23

• Multiplex approaches that simultaneously measure FGF23 alongside other mineral metabolism markers may improve clinical utility

What is the potential for targeting FGF23 therapeutically?

The question of whether FGF23 should be considered a therapeutic target is complex:

• Current clinical applications of FGF23 measurement are established in:

  • Diagnosis of hereditary hypophosphatemic rickets

  • Diagnosis and follow-up of tumor-induced osteomalacia

• Potential therapeutic applications:

  • In CKD, reducing elevated FGF23 might mitigate cardiovascular risk

  • In hematopoietic stem cell transplantation, manipulating FGF23 might improve stem cell mobilization

  • In hereditary hypophosphatemic disorders, anti-FGF23 antibodies have shown promise