Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Increased angiogenesis has been associated with various inflammatory disease states including rheumatoid arthritis (RA), and it has been considered as one of main factors for pathogenesis of RA. Angiogenic mediators excessively released by various types of cells within the synovium possibly activate vascular endothelial cells (ECs) in RA subsequently resulting in pannus formation. A series of our previous studies has demonstrated that connective tissue growth factor (CTGF) was massively produced on synovial fibroblasts in RA. In addition, we have also demonstrated that excessive CTGF contributed to aberrant activation of osteoclasts in RA, suggesting that CTGF is an important factor for pathogenesis of RA. To extend our research project regarding CTGF function on RA pathogenesis, this study was conducted to clarify whether CTGF relates to aberrant angiogenesis of RA.
Methods: Various effects of CTGF on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs). The efficacy of CTGF on vascularization, proliferation, and migration were evaluated by tube formation assay, BrdU assay, and boyden chamber assay respectively. Regulation of CTGF production by proinflammatory cytokines (IL-6 and TNF-a) on HUVECs was evaluated by quantitative RT-PCR and immunoblotting. Notch-1 activation induced by CTGF on HUVECs was evaluated by immunoboltting and IIF.
Results: CTGF had positive effects for vascularization, proliferation, and migration on HUVECs. IL-6 upregulated CTGF expression even though TNF-a oppositely downregulated CTGF expression on HUVECs. Interestingly, we found that CTGF related to not only Notch-1 production but also activation of Notch-1.
Conclusion: Our data indicated that CTGF is massively produced on not only fibroblasts but also vascular endothelial cells in synovial tissue of RA due to aberrant regulation of proinflamatory cytokines. Excessive CTGF production possibly causes aberrant angiogenesis and osteoclasts activation in synovial tissue in RA. In addition, we newly found that CTGF related to production and activation of Notch-1which has been recently postulated as important factor of angiogenesis in RA. The present study clearly demonstrated that CTGF significantly related to angiogenesis through direct or indirect mechanisms, suggesting that CTGF plays an important role for disease progression of RA. CTGF may become a new target molecule for treatment of RA.
Refernces:
- Nozawa et al. Connective tissue growth factor promotes articular damage by increased osteoclastogenesis in patients with rheumatoid arthritis. Arthritis Res Ther. 2009;11(6):R174.
- Nozawa et al. Inhibition of connective tissue growth factor ameliorates rheumatoid arthritis ina murine model. Arthritis Rheum. 2013 Feb 22. doi: 10.1002/art.37902. [Epub ahead of print]
-
Sekigawa et al. Protein biomarker analysis by mass spectrometry inpatients with rheumatoid arthritis receiving anti-tumor necrosis factor-alpha antibody therapy. Clin Exp Rheumatol 2008, 26:261-267.
Disclosure:
K. Nozawa,
None;
M. Fujishiro,
None;
A. Yamaguchi,
None;
M. Kawasaki,
None;
K. Iwabuchi,
None;
M. Yanagida,
None;
K. Ikeda,
None;
S. Morimoto,
None;
Y. Takasaki,
None;
I. Sekigawa,
None.
« Back to 2013 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/connective-tissue-growth-factor-promotes-angiogenesis-through-increased-notch-1-signaling-in-rheumatoid-arthritis/