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

Kanako Wakahashi, Kentaro Minagawa, Yuko Kawano, Hiroki Kawano, Tomohide Suzuki, Shinichi Ishii, Akiko Sada, Noboru Asada, Mari Sato, Shigeaki Kato, Kotaro Shide, Kazuya Shimoda, Toshimitsu Matsui and Yoshio Katayama

Key Points

  • Macrophages whose differentiation is skewed by VDR signaling are the key drivers for myofibroblasts in vivo.

  • Macrophages and VDR can be therapeutic targets in JAK2V617F-driven myelofibrosis.

Publisher's Note: There is a Blood Commentary on this article in this issue.

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 an 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–positive 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 MPNs likely in a transforming growth factor-β1– or megakaryocyte-independent manner. These results suggest that VDR and macrophages may be novel therapeutic targets for MPNs with myelofibrosis.

  • Submitted September 22, 2018.
  • Accepted January 27, 2019.
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