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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1849-1856.
Prepublished online as a Blood First Edition Paper on May 18, 2006; DOI 10.1182/blood-2006-04-016030.
 Previous Article | Next Article 
Submitted December 21, 2005
Accepted May 1, 2006
Signaling of vascular endothelial growth factor receptor-
1 tyrosine kinase promotes rheumatoid arthritis through
activation of monocyte/macrophages
Masato Murakami, Shinobu Iwai, Sachie Hiratsuka, Mai Yamauchi, kazuhide Nakamura, Yoichiro Iwakura, and Masabumi Shibuya*
Institute of Madical Science, University of Tokyo
Tokyo Women's Medical University
Kirin Brewery Co.Ltd.
* Corresponding author; email: shibuya{at}ims.u-tokyo.ac.jp.
Vascular endothelial growth factor (VEGF) and VEGF
receptor-1 (VEGFR-1/Flt-1) were shown to be involved in
pathological angiogenesis, particularly rheumatoid
arthritis (RA). However, the molecular basis of their
actions is not fully understood. Here we report that in
a murine model of RA, deletion of the tyrosine kinase
(TK) domain of VEGFR-1 decreased the incidence and
clinical symptoms of RA. Pathological symptoms, such as
synovial hyperplasia, inflammatory infiltrates, pannus
formation and cartilage/bone destruction became milder
in Vegfr-1 tk-/- mice compared with Wild-type (Wt) mice
in the Human T-cell Leukemia Virus-1 pX (HTLV-1 pX)
induced chronic models. VEGFR-1 TK-deficient bone marrow
cells showed a suppression of multi-lineage colony
formation. Furthermore, macrophages induced to
differentiate in vitro showed a decrease in
immunological reactions such as phagocytosis and the
secretion of Interleukin-6 (IL-6) and VEGF-A. Treatment
of this RA model with a small molecule inhibitor for
VEGFR TK, KRN951, also attenuated the arthritis. These
results indicate that the VEGFR-1 TK signaling modulates
the proliferation of bone marrow hematopoietic cells and
immunity of monocyte/macrophages, and promotes chronic
inflammation, which may be a new target in the treatment
of RA.
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