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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1619-1629 |
| Number of pages | 11 |
| Journal | Blood |
| Volume | 133 |
| Issue number | 15 |
| DOIs | |
| State | Published - Apr 11 2019 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Biochemistry
- Immunology
- Hematology
- Cell Biology
Cite this
}
Vitamin D receptor–mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis. / Wakahashi, Kanako; Minagawa, Kentaro; Kawano, Yuko; Kawano, Hiroki; Suzuki, Tomohide; Ishii, Shinichi; Sada, Akiko; Asada, Noboru; Sato, Mari; Kato, Shigeaki; Shide, Kotaro; Shimoda, Kazuya; Matsui, Toshimitsu; Katayama, Yoshio.
In: Blood, Vol. 133, No. 15, 11.04.2019, p. 1619-1629.Research output: Contribution to journal › Article
TY - JOUR
T1 - Vitamin D receptor–mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis
AU - Wakahashi, Kanako
AU - Minagawa, Kentaro
AU - Kawano, Yuko
AU - Kawano, Hiroki
AU - Suzuki, Tomohide
AU - Ishii, Shinichi
AU - Sada, Akiko
AU - Asada, Noboru
AU - Sato, Mari
AU - Kato, Shigeaki
AU - Shide, Kotaro
AU - Shimoda, Kazuya
AU - Matsui, Toshimitsu
AU - Katayama, Yoshio
PY - 2019/4/11
Y1 - 2019/4/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064814012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064814012&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-09-876615
DO - 10.1182/blood-2018-09-876615
M3 - Article
C2 - 30718230
AN - SCOPUS:85064814012
VL - 133
SP - 1619
EP - 1629
JO - Blood
JF - Blood
SN - 0006-4971
IS - 15
ER -