Myelodysplastic syndromes and bone loss in mice and men

Weidner, Heike; Rauner, Martina; Trautmann, Franziska; Schmitt, Jochen; Balaian, Ekaterina; Mies, Anna; Helas, Susann; Baschant, Ulrike; Khandanpour, Cyrus; Bornhäuser, Martin; Hofbauer, Lorenz C.; Platzbecker, Uwe

doi:10.1038/leu.2017.7

Cited by 29 publications

(29 citation statements)

References 15 publications

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“…However, NHD13 mice exhibited no changes in skeletal structure nor osteoblastic bone formation and osteoclastic bone resorption, indicating that the expanded populations do not generate functional bone-forming cells [89]. Recently, Weidner et al reported decreased trabecular bone volume in younger NHD13 mice at 2 month of age when cytopenias are not yet prominent in this model [90]. This suggests that mesenchymal-osteolineage dysfunction in NHD13 mice alters skeletal structure in a time-dependent manner, resulting in early disruption of bone microarchitecture that precedes overt multi-lineage cytopenias by approximately 4 months of age [88].…”

Section: Mesenchymal-osteolineage Dysfunction In Murine Models Of Mdsmentioning

confidence: 99%

“…A link between bone alterations and MDS also exists in humans as osteoblast numbers and serum osteocalcin are lower in patients with MDS compared to age-match healthy individuals [95] and MDS is more prevalent in elderly individuals with osteoporosis compared to those without osteoporosis [90]. Moreover, skeletal defects due to inactivating SBDS mutations in Shwachman-Diamond syndrome (SDS) are associated MDS and AML development early in life, while osteoprogenitor-specific knockout of Sbds in mice induced myelodysplasia [55].…”

Section: Mesenchymal-osteolineage Dysfunction In Murine Models Of Mdsmentioning

confidence: 99%

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The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Calvi

2017

Experimental Hematology

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Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem and progenitor cells and represent the most common cause of acquired marrow failure. Hallmarked by ineffective hematopoiesis, dysplastic marrow, and risk of transformation to acute leukemia, MDS remains a poorly treated disease. Although identification of hematopoietic aberrations in human MDS has contributed significantly to our understanding of MDS pathogenesis, evidence now identify the bone marrow microenvironment (BMME) as another key contributor to disease initiation and progression. With improved understanding of the BMME, we are beginning to refine the role of the hematopoietic niche in MDS. Despite genetic diversity in MDS, interaction between MDS and the BMME appears to be a common disease feature, and therefore represents an appealing therapeutic target. Further understanding of the interdependent relationship between MDS and its niche is needed to delineate the mechanisms underlying hematopoietic failure and how the microenvironment can be clinically targeted. This review will provide an overview of data from human MDS and murine models supporting a role for BMME dysfunction at several steps of disease pathogenesis. While no models or human studies so far have combined all these findings, we will review current data identifying BMME involvement in each step of MDS pathogenesis, organized to reflect the chronology of BMME contribution as the normal hematopoietic system becomes myelodysplastic and MDS progresses to marrow failure and transformation. Although microenvironmental heterogeneity and dysfunction certainly add complexity to this syndrome, data are already demonstrating that targeting microenvironmental signals may represent novel therapeutic strategies for MDS treatment.

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Section: Mesenchymal-osteolineage Dysfunction In Murine Models Of Mdsmentioning

confidence: 99%

Section: Mesenchymal-osteolineage Dysfunction In Murine Models Of Mdsmentioning

confidence: 99%

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Calvi

2017

Experimental Hematology

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“…Keeping in mind the contradictory data about the action of erythropoietin on bone in grown vertebrates, and based on the observation that MDS patients, who are mostly elderly and often display excessive erythropoietin levels, as well as osteoporosis, 23 we aimed to evaluate the influence of erythropoietin on osteoblasts derived from patients with MDS to clarify the potential association between erythropoietin levels and their effects on bone formation.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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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“…Afterward, osteoblasts deriving from mesenchymal stem cells (MSC) produce a new and nonmineralized bone matrix (osteoid) that is gradually mineralized, thus providing rigidity (7). Bone remodeling and bone mass maintenance are critically affected in MDS, as patients with MDS have a 2-fold higher risk to develop fragility fractures than their age-matched controls (8).…”

Section: Introductionmentioning

confidence: 99%

“…This mouse overexpresses the NUP98/HOXD13 fusion protein in hematopoietic cells and develops MDS-like features such as peripheral cytopenias and dysplasia in blood as well as bone marrow cells at the age of 4-6 months, which later also transforms into acute myeloid leukemia (19). Recently, we depicted microstructural abnormalities in the bone microenvironment of NHD13 mice (8); however, the underlying cellular and molecular mechanisms were not explored. Using these mice, we show that myelodysplastic mice have a high fraction of nonmineralized bone in the presence of an increased number of osteoblasts, which coincides with high serum levels of fibroblast growth factor-23 (FGF-23), a hormone regulating phosphate homeostasis and bone mineralization (20,21).…”

Section: Introductionmentioning

confidence: 99%

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

Weidner¹,

Baschant²,

Lademann³

et al. 2020

JCI Insight

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Myelodysplastic syndromes and bone loss in mice and men

Cited by 29 publications

References 15 publications

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

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

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

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