[HTML][HTML] Erythropoietin inhibits osteoblast function in myelodysplastic syndromes via the canonical Wnt pathway

E Balaian, M Wobus, H Weidner, U Baschant… - …, 2018 - ncbi.nlm.nih.gov
E Balaian, M Wobus, H Weidner, U Baschant, M Stiehler, G Ehninger, M Bornhäuser
Haematologica, 2018ncbi.nlm.nih.gov
The effects of erythropoietin on osteoblasts and bone formation are controversial. Since
patients with myelodysplastic syndromes often display excessively high erythropoietin
levels, we aimed to analyze the effect of erythropoietin on osteoblast function in
myelodysplastic syndromes and define the role of Wnt signaling in this process. Expression
of osteoblast-specific genes and subsequent osteoblast mineralization was increased in
mesenchymal stromal cells from healthy young donors by in vitro erythropoietin treatment …
Abstract
The effects of erythropoietin on osteoblasts and bone formation are controversial. Since patients with myelodysplastic syndromes often display excessively high erythropoietin levels, we aimed to analyze the effect of erythropoietin on osteoblast function in myelodysplastic syndromes and define the role of Wnt signaling in this process. Expression of osteoblast-specific genes and subsequent osteoblast mineralization was increased in mesenchymal stromal cells from healthy young donors by in vitro erythropoietin treatment. However, erythropoietin failed to increase osteoblast mineralization in old healthy donors and in patients with myelodysplasia, whereas the basal differentiation potential of the latter was already significantly reduced compared to that of age-matched controls (P< 0.01). This was accompanied by a significantly reduced expression of genes of the canonical Wnt pathway. Treatment of these cells with erythropoietin further inhibited the canonical Wnt pathway. Exposure of murine cells (C2C12) to erythropoietin also produced a dose-dependent inhibition of TCF/LEF promoter activity (maximum at 500 IU/mL,− 2.8-fold; P< 0.01). The decreased differentiation capacity of erythropoietin-pretreated mesenchymal stromal cells from patients with myelodysplasia could be restored by activating the Wnt pathway using lithium chloride or parathyroid hormone. Its hematopoiesis-supporting capacity was reduced, while reactivation of the canonical Wnt pathway in mesenchymal stromal cells could reverse this effect. Thus, these data demonstrate that erythropoietin modulates components of the osteo-hematopoietic niche in a context-dependent manner being anabolic in young, but catabolic in mature bone cells. Targeting the Wnt pathway in patients with myelodysplastic syndromes may be an appealing strategy to promote the functional capacity of the osteo-hematopoietic niche.
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