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* Department of Internal Medicine, Division of Rheumatology, School of Medicine, Catholic University of Korea, Seoul, Korea;
Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Korea;
Laboratory of Cell Cycle Control, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; and
Institute of Biomedical Science and Technology, Konkuk University, Seoul, Korea
Rheumatoid arthritis (RA) synoviocytes are resistant to apoptosis and exhibit a transformed phenotype, which might be caused by chronic exposure to genotoxic stimuli including reactive oxygen species and growth factors. In this study, we investigated the role of vascular endothelial growth factor165 (VEGF165), a potent angiogenic factor, and its receptor in the apoptosis of synoviocytes. We demonstrated here that neuropilin-1, rather than fms-like tyrosine kinase-1 and kinase insert domain-containing receptor, is the major VEGF165 receptor in the fibroblast-like synoviocytes. Neuropilin-1 was highly expressed in the lining layer, infiltrating leukocytes, and endothelial cells of rheumatoid synovium. The production of VEGF165, a ligand for neuropilin, was significantly higher in the RA synoviocytes than in the osteoarthritis synoviocytes. The ligation of recombinant VEGF165 to its receptor prevented the apoptosis of synoviocytes induced by serum starvation or sodium nitroprusside (SNP). VEGF165 rapidly triggered phospho-Akt and phospho-ERK activity and then induced Bcl-2 expression in the rheumatoid synoviocytes. The Akt or ERK inhibitor cancelled the protective effect of VEGF165 on SNP-induced synoviocyte apoptosis. Moreover, VEGF165 blocks SNP-induced Bcl-2 down-regulation as well as SNP-induced Bax translocation from the cytosol to the mitochondria. The down-regulation of the neuropilin-1 transcripts by short interfering RNA caused spontaneous synoviocyte apoptosis, which was associated with both the decrease in Bcl-2 expression and the increase in Bax translocation to mitochondria. Collectively, our data suggest that the interaction of VEGF165 with neuropilin-1 is crucial to the survival of rheumatoid synoviocytes and provide important implications for the abnormal growth of synoviocytes and therapeutic intervention in RA.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grant A050196 from the Ministry of Health and Welfare of the Republic of Korea.
2 Address correspondence and reprint requests to Dr. Chul-Soo Cho, Department of Internal Medicine, School of Medicine, Division of Rheumatology, Catholic University of Korea, St. Mary’s Hospital, 62 Youido-Dong, Youngdeungpo-Ku, Seoul 150-713, South Korea. E-mail address: chocs{at}catholic.ac.kr
3 Abbreviations used in this paper: RA, rheumatoid arthritis; FLS, fibroblast-like synoviocytes; HBD, heparin-binding domain; NP-1, neuropilin-1; SNP, sodium nitroprusside; VEGF, vascular endothelial growth factor; Flt-1, fms-like tyrosine kinase; KDR, kinase insert domain-containing receptor; OA, osteoarthritis; ITSA, insulin-transferrin-selenium A pAkt, phospho-Akt; pERK, phospho-ERK.
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  L. Q.M. Chow and S. G. Eckhardt In Reply J. Clin. Oncol., July 1, 2007; 25(19): 2859 - 2861. [Full Text] [PDF]
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