Format

Send to

Choose Destination
Blood. 2019 Feb 4. pii: blood-2018-09-876615. doi: 10.1182/blood-2018-09-876615. [Epub ahead of print]

Vitamin D receptor-mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis.

Author information

1
Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
2
Center for Regional Cooperation, Iwaki Meisei University, Fukushima, Japan.
3
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
4
Department of Hematology, Nishiwaki Municipal Hospital, Nishiwaki, Japan.
5
Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; katayama@med.kobe-u.ac.jp.

Abstract

Myelofibrosis in myeloproliferative neoplasms (MPNs) with mutations such as JAK2V617F is an unfavorable sign for uncontrollable disease progression in the clinic and is complicated with osteosclerosis whose pathogenesis is largely unknown. Because several studies have revealed that macrophages are indispensable supporter for bone forming osteoblasts, we speculated that macrophages might play a significant role in the proliferation of collagen-producing myofibroblasts in marrow fibrotic tissues. Here, we show that myelofibrosis critically depends on macrophages whose differentiation is skewed by vitamin D receptor (VDR) signaling. In our novel myelofibrosis model established by transplantation of VDR+/+ hematopoietic stem/progenitor cells into VDR-/- mice, donor-derived F4/80+ macrophages proliferated together with recipient-derived α-smooth muscle actin (α-SMA)+ myofibroblasts, both of which comprised fibrotic tissues with an indistinguishable spindle-shaped morphology. Interfering VDR signals, such as low vitamin D diet and VDR deficiency in donor cells, as well as macrophage depletion prevented myelofibrosis in this model. These interventions also ameliorated myelofibrosis in JAK2V617F-driven murine MPN likely in a transforming growth factor-β1 (TGF-β1)- or megakaryocyte-independent manner. These results suggest that VDR and macrophages may be novel therapeutic targets for MPNs with myelofibrosis.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center