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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. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2006-04-016030v1 108/6/1849    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Murakami, M. Articles by Shibuya, M. Search for Related Content PubMed PubMed Citation Articles by Murakami, M. Articles by Shibuya, M. Related Collections Hematopoiesis and Stem Cells Phagocytes Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages Masato Murakami, Shinobu Iwai, Sachie Hiratsuka, Mai Yamauchi, Kazuhide Nakamura, Yoichiro Iwakura, and Masabumi Shibuya From the Division of Genetics and Division of Cell Biology, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Japan; Department of Pharmacology, Tokyo Women's Medical University, Japan; and Pharmaceutical Developmental Laboratories, Kirin Brewery, Gunma, Japan. 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 (HTLV-1) pX–induced chronic models. VEGFR-1 TK-deficient bone marrow cells showed a suppression of multilineage colony formation. Furthermore, macrophages induced to differentiate in vitro showed a decrease in immunologic 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 monocytes/macrophages and promotes chronic inflammation, which may be a new target in the treatment of RA. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Q. Guo, J. J. Carrero, X. Yu, P. Barany, A. R. Qureshi, M. Eriksson, B. Anderstam, M. Chmielewski, O. Heimburger, P. Stenvinkel, et al. Associations of VEGF and its receptors sVEGFR-1 and -2 with cardiovascular disease and survival in prevalent haemodialysis patients Nephrol. Dial. Transplant., June 26, 2009; (2009) gfp315v1. [Abstract] [Full Text] [PDF] M. C. BOSCO, S. DELFINO, F. FERLITO, M. PUPPO, A. GREGORIO, C. GAMBINI, M. GATTORNO, A. MARTINI, and L. 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[Abstract] [Full Text] [PDF] M. Murakami, Y. Zheng, M. Hirashima, T. Suda, Y. Morita, J. Ooehara, H. Ema, G.-H. Fong, and M. Shibuya VEGFR1 Tyrosine Kinase Signaling Promotes Lymphangiogenesis as Well as Angiogenesis Indirectly via Macrophage Recruitment Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 658 - 664. [Abstract] [Full Text] [PDF] T. Schomber, L. Kopfstein, V. Djonov, I. Albrecht, V. Baeriswyl, K. Strittmatter, and G. Christofori Placental Growth Factor-1 Attenuates Vascular Endothelial Growth Factor-A Dependent Tumor Angiogenesis during {beta} Cell Carcinogenesis Cancer Res., November 15, 2007; 67(22): 10840 - 10848. [Abstract] [Full Text] [PDF] O. Raisky, A. I. Nykanen, R. Krebs, M. Hollmen, M. A.I. Keranen, J. M. Tikkanen, R. Sihvola, L. Alhonen, P. Salven, Y. Wu, et al. VEGFR-1 and -2 Regulate Inflammation, Myocardial Angiogenesis, and Arteriosclerosis in Chronically Rejecting Cardiac Allografts Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 819 - 825. 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