Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes
Heike Weidner, Ulrike Baschant, Franziska Lademann, Maria G. Ledesma Colunga, Ekaterina Balaian, Christine Hofbauer, Barbara M. Misof, Paul Roschger, Stéphane Blouin, William G. Richards, Uwe Platzbecker, Lorenz C. Hofbauer, Martina Rauner
Heike Weidner, Ulrike Baschant, Franziska Lademann, Maria G. Ledesma Colunga, Ekaterina Balaian, Christine Hofbauer, Barbara M. Misof, Paul Roschger, Stéphane Blouin, William G. Richards, Uwe Platzbecker, Lorenz C. Hofbauer, Martina Rauner
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Research Article Bone biology Hematology

Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are clonal malignant hematopoietic disorders in the elderly characterized by ineffective hematopoiesis. This is accompanied by an altered bone microenvironment, which contributes to MDS progression and higher bone fragility. The underlying mechanisms remain largely unexplored. Here, we show that myelodysplastic NUP98‑HOXD13 (NHD13) transgenic mice display an abnormally high number of osteoblasts, yet a higher fraction of nonmineralized bone, indicating delayed bone mineralization. This was accompanied by high fibroblast growth factor-23 (FGF-23) serum levels, a phosphaturic hormone that inhibits bone mineralization and erythropoiesis. While Fgf23 mRNA expression was low in bone, brain, and kidney of NHD13 mice, its expression was increased in erythroid precursors. Coculturing these precursors with WT osteoblasts induced osteoblast marker gene expression, which was inhibited by blocking FGF-23. Finally, antibody-based neutralization of FGF-23 in myelodysplastic NHD13 mice improved bone mineralization and bone microarchitecture, and it ameliorated anemia. Importantly, higher serum levels of FGF‑23 and an elevated amount of nonmineralized bone in patients with MDS validated the findings. C‑terminal FGF‑23 correlated negatively with hemoglobin levels and positively with the amount of nonmineralized bone. Thus, our study identifies FGF-23 as a link between altered bone structure and ineffective erythropoiesis in MDS with the prospects of a targeted therapeutic intervention.

Authors

Heike Weidner, Ulrike Baschant, Franziska Lademann, Maria G. Ledesma Colunga, Ekaterina Balaian, Christine Hofbauer, Barbara M. Misof, Paul Roschger, Stéphane Blouin, William G. Richards, Uwe Platzbecker, Lorenz C. Hofbauer, Martina Rauner

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Figure 4

Erythroid precursors of NHD13 mice express high Fgf‑23 and activate osteoblasts.

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Erythroid precursors of NHD13 mice express high Fgf‑23 and activate oste...
(A) Primary bone marrow cells of 6‑month‑old WT (WT) and NUP98/HOXD13 (NHD13) mice were used to assess the amount of Ter119-positive cells by flow cytometry (n = 12–13). (B) In Ter119-positive cells, gene expression of Fgf23, Fgfr1–4, and Klotho were determined by quantitative PCR (n = 8–10). (C and D) Erythroid differentiation (n = 7–9), as well as apoptosis (n = 5–7), in erythroid maturation stages was analyzed using flow cytometry. (E) In addition, erythroid precursors of WT and NHD13 mice were cocultured with WT osteoblast in the presence or absence of FGF‑23 antibodies, and the Alp (n = 12–17) as well as Runx2 (n = 15–18) expression was measured in the osteoblasts. Data are shown as mean ± SD of 3 independent experiments. In B, the dotted line represents WT levels. Statistical analysis was performed by the 2-sided Student′s t test or 1-way ANOVA followed by Bonferroni’s multiple comparison. *P < 0.05; **P < 0.01; ***P < 0.001 vs. WT.