@article{fdd9d29a0ffb4e98b15a262e52568664,
title = "Vitamin D receptor–mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis",
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 VDR1/1 hematopoietic stem/progenitor cells into VDR2/2 mice, donor-derived F4/801 macrophages proliferated together with recipient-derived a-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-b1– or megakaryocyte-independent manner. These results suggest that VDR and macrophages may be novel therapeutic targets for MPNs with myelofibrosis.",
author = "Kanako Wakahashi and Kentaro Minagawa and Yuko Kawano and Hiroki Kawano and Tomohide Suzuki and Shinichi Ishii and Akiko Sada and Noboru Asada and Mari Sato and Shigeaki Kato and Kotaro Shide and Kazuya Shimoda and Toshimitsu Matsui and Yoshio Katayama",
note = "Funding Information: This work was supported by PRESTO, the Japan Science and Technology Agency (#JPMJPR12M7 [Y. Katayama]), a CREST grant from AMED (#JP18gm0910012h2 [Y. Katayama]), and the Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (#15H04856, #18H02837 [Y. Katayama]) and for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology in Japan (#25118715 [Y. Katayama]). This work was also supported by the Daiichi Sankyo Foundation of Life Science, the Itochube Foundation, Novartis Pharma research grants, the Astellas Foundation for Research on Metabolic Disorders, and the SENSHIN Medical Research Foundation (Y. Katayama). Funding Information: The authors thank Paul S. Frenette (Albert Einstein College of Medicine, New York) for the useful comments on the manuscript. This work was supported by PRESTO, the Japan Science and Technology Agency (#JPMJPR12M7 [Y. Katayama]), a CREST grant from AMED (#JP18gm0910012h2 [Y. Katayama]), and the Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (#15H04856, #18H02837 [Y. Katayama]) and for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology in Japan (#25118715 [Y. Katayama]). This work was also supported by the Daiichi Sankyo Foundation of Life Science, the Itochube Foundation, Novartis Pharma research grants, the Astellas Foundation for Research on Metabolic Disorders, and the SENSHIN Medical Research Foundation (Y. Katayama). Publisher Copyright: {\textcopyright} 2019 by The American Society of Hematology.",
year = "2019",
month = apr,
day = "11",
doi = "10.1182/blood-2018-09-876615",
language = "English (US)",
volume = "133",
pages = "1619--1629",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "15",
}