Erythroid FGF23 Directly Inhibits Red Cell Production in Mouse Models

The Dual Role of Fibroblast Growth Factor 23 in Mineral Metabolism and Erythropoiesis

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates systemic phosphate homeostasis and vitamin D metabolism [1, 2]. In clinical practice, elevated circulating levels of this hormone are frequently observed in patients with iron deficiency anemia and chronic kidney disease, where they correlate with adverse cardiovascular outcomes and renal disease progression [3, 4]. While oral iron supplementation can effectively lower hormone concentrations, certain intravenous iron formulations paradoxically trigger a surge in the intact, biologically active form of the protein, often leading to renal phosphate wasting and symptomatic hypophosphatemia [5, 6]. This complex relationship suggests that the hormone may exert physiological effects beyond mineral regulation, particularly within the hematopoietic compartment [7]. A new study now clarifies the specific cellular source and local mechanism by which this factor directly impairs red blood cell maturation.

Differentiating Bone and Erythroid Sources of FGF23

Fibroblast growth factor 23 is primarily recognized as a phosphate-regulating hormone produced by osteocytes, the mature bone cells responsible for mineral homeostasis. Under physiological conditions, this hormone maintains systemic phosphate balance by promoting renal excretion. However, the researchers observed that in pathological states such as iron deficiency anemia and chronic kidney disease, erythroid cells also become a significant source of FGF23 production. This secondary site of synthesis suggests a localized role for the hormone within the bone marrow microenvironment that is distinct from its systemic endocrine functions in mineral metabolism. To isolate the specific contributions of these two cellular sources, the study utilized conditional deletion of Fgf23, a genetic technique that allows for the inactivation of a gene only within specific tissue types. The researchers compared mice with the gene deleted in osteocytes, known as Fgf23Dmp1-cKO, against those with the gene deleted in erythroid cells, designated as Fgf23HbB-cKO. These cohorts were further divided and fed either a control diet or an iron deficient diet to simulate the conditions of iron deficiency anemia. This experimental design allowed the team to track how different cell populations respond to iron stress and how those responses influence circulating hormone levels. The findings revealed a critical divergence in how these tissues process the hormone during iron deficiency. In the iron deficient mice, osteocytes were identified as the primary source of circulating intact FGF23 (iFGF23), which is the biologically active form of the protein. Conversely, the researchers found that erythroid cells in the iron deficient state primarily produce FGF23 cleaved peptides, which are the inactive fragments resulting from the breakdown of the intact hormone. This distinction is clinically relevant because it suggests that while bone-derived hormone may drive systemic mineral disturbances, the erythroid-derived peptides and their precursors may play a more localized, paracrine role (local cell-to-cell communication) in regulating red blood cell production within the marrow.

Local Hormone Production Drives Anemia Severity

Clinical observations in patients with iron deficiency anemia and chronic kidney disease have long indicated that rising circulating levels of FGF23 are negatively associated with erythropoiesis, the process of red blood cell production. To investigate whether this association is causal and tissue-specific, the researchers employed mouse models to isolate the effects of the hormone produced in bone versus that produced in the marrow. The study found that erythroid-specific deletion of Fgf23 corrected anemia in mice fed an iron-deficient diet, effectively restoring red cell parameters despite the systemic iron deficit. In contrast, osteocyte-specific deletion of Fgf23 failed to correct anemia in iron-deficient mice, demonstrating that the hormone produced by bone cells does not exert the same inhibitory effect on red cell production as the hormone produced locally within the erythroid lineage. The researchers further validated this local regulatory mechanism by manipulating hormone levels in mice on a standard control diet. They observed that overexpression of Fgf23 specifically in erythroid cells induced anemia in mice on a control diet, whereas the overexpression of the hormone in osteocytes did not alter red blood cell status. This suggests a paracrine mechanism, where the hormone acts directly on neighboring cells within the bone marrow microenvironment. The biological activity of this pathway is heavily dependent on Furin, the specific proprotein convertase enzyme responsible for FGF23 cleavage, which is the process of breaking down the intact hormone into inactive fragments. When the researchers utilized erythroid-specific deletion of Furin (FurinHbB-cKO), they observed an increased production of intact FGF23 from erythroid cells, as the hormone could no longer be effectively cleaved into its inactive forms. This accumulation of the active, intact hormone had significant clinical consequences in the animal models. The erythroid-specific deletion of Furin aggravated iron-deficiency-induced anemia, leading to more severe reductions in hemoglobin and red cell counts than those seen in iron-deficient mice with functional Furin. By preventing the breakdown of the hormone within the marrow, the researchers effectively increased the local concentration of intact FGF23, which then acted as a potent inhibitor of erythroid progenitor differentiation.

Mitochondrial Dysfunction and the FGFR1 Signaling Pathway

To elucidate the cellular mechanisms behind these observations, the researchers conducted in vitro experiments using erythroid progenitors, which are the immature precursor cells that must undergo a complex maturation process to become functional red blood cells. The study found that intact FGF23 dose-dependently blocked the differentiation of erythroid progenitors in culture, effectively halting the transition from immature precursors to mature erythrocytes. This dose-response relationship suggests that the local concentration of the intact hormone in the bone marrow directly dictates the degree of erythropoietic suppression, providing a clear link between elevated hormone levels and the severity of anemia. The researchers further identified the intracellular pathway responsible for this maturation arrest, demonstrating that intact FGF23 triggered mitochondrial dysfunction in erythroid progenitors. Because red blood cell maturation is an energy-intensive process requiring robust mitochondrial activity for heme synthesis and metabolic regulation, this cellular failure had significant consequences. The study established that this mitochondrial dysfunction led to impaired erythropoiesis, as the progenitor cells were unable to meet the metabolic demands necessary for survival and maturation. This finding shifts the understanding of the hormone from a simple signaling molecule to a direct disruptor of the metabolic machinery within the erythroid lineage. Finally, the study pinpointed the specific molecular target through which the hormone exerts these inhibitory effects. The researchers observed that the inhibitory effects of intact FGF23 on erythroid differentiation were fully suppressed by co-treatment with an FGFR1 inhibitor, a pharmacological agent that blocks fibroblast growth factor receptor 1. By preventing the hormone from binding to FGFR1 on the surface of erythroid precursors, the researchers were able to completely restore normal red cell production in the presence of high hormone levels. This confirms that the hormone contributes to anemia via direct paracrine FGFR1 activation in erythroid precursors, identifying this receptor as a potential therapeutic target for treating anemia in patients with iron deficiency or chronic kidney disease.

Implications for Chronic Kidney Disease Management

The clinical implications of these findings extend beyond iron deficiency to the management of chronic kidney disease, where anemia is a frequent and debilitating complication. To investigate this, the researchers utilized an animal model of progressive chronic kidney disease to observe the effects of local hormone production on hemoglobin levels. The study demonstrated that the erythroid-specific deletion of Fgf23 in an animal model of progressive chronic kidney disease prevented the development of anemia of chronic kidney disease. This finding is particularly significant because it suggests that the hormone produced within the bone marrow itself, rather than the systemic hormone originating from bone tissue, is a primary driver of the drop in red blood cell mass as renal function declines. By removing the gene responsible for the hormone only within the erythroid lineage, the researchers maintained higher hemoglobin levels despite the presence of advancing renal failure. These results clarify the pathophysiology of renal anemia by establishing that erythroid-expressed FGF23 acts as a negative regulator of erythropoiesis via direct paracrine FGFR1 activation in erythroid precursors. In this context, paracrine signaling refers to the local cell-to-cell communication where the hormone produced by erythroid cells acts directly on neighboring precursor cells within the bone marrow microenvironment. This local activation of fibroblast growth factor receptor 1 (FGFR1) creates a suppressive niche that halts red cell maturation. For the practicing clinician, this identifies the hormone not merely as a biomarker of phosphate imbalance or renal stress, but as a direct mediator of bone marrow dysfunction. Targeting this local signaling pathway may offer a therapeutic strategy for patients with refractory anemia who do not achieve adequate responses to standard iron supplementation or erythropoietin-stimulating agents.

References

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