Background/Purpose: Aberrant angiogenesis has been considered as one of important factors for pathogenesis of rheumatoid arthritis (RA). Several angiogenetic mediators are reported to be massively expressed in synovial tissues of RA patients. Among the mediators, Notch-1 has been reported as one of important angiogenetic mediators in RA. A series of our previous studies have demonstrated that connective tissue growth factor (CTGF) was highly expressed in synovial tissue of RA. CTGF is a multifunctional cytokine and well known as strong mediator for fibrosis. Although we found that CTGF played an important role for the disease progression of RA by multiple mechanisms such as osteoclastogenesis, CTGF interestingly has also been reported as a potent angiogenetic mediator in other diseases. Therefore, this study was conducted to clarify whether CTGF associates with angiogenesis of RA, especially in terms of relation to Notch-1. Furthermore, the therapeutic efficacy of CTGF blockade for prevention of aberrant angiogenesis was also evaluated in animal model of RA.

Methods:

Synovial tissue samples of RA patients were used for immunohistochemical analysis. CTGF association for angiogenesis was evaluated by tube formation assay and Boyden chamber assay using human umbilical vein endothelial cells (HUVECs) in vitro. CTGF-mediated Notch-1 activation were evaluated by immunofluorescence, immunoblotting, and quantitative RT-PCR analysis in HUVECs. Therapeutic efficacy of CTGF blockade for prevention of increased angiogenesis was evaluated in collagen induced arthritis (CIA) mice by administration of the neutralizing anti-CTGF antibodies.

Results: Synovial tissues of RA patients showed upregulation of Notch-1 pathway indicated by strong expression of Notch-1, Notch-1 transmembrane domain (NICD), and DLL-4. CTGF functioned as angiogenetic mediator and was able to activate Notch-1 signaling pathway in vitro. Administration of neutralizing anti-CTGF antibodies prevented the development of angiogenesis through inhibition of Notch-1 expression in CIA mice.

Conclusion: CTGF is able to mediate activation signal against Notch-1 which has been recently postulated as important factor of angiogenesis in RA. CTGF was considered to play an important role for aberrant angiogenesis of RA in combination with Notch-1. CTGF may become a novel target molecule for treatment of RA as CTGF blockade may ameliorate RA by multiple therapeutic mechanisms including suppression of aberrant angiogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/connective-tissue-growth-factor-associates-with-angiogenesis-through-notch-1-activation-in-rheumatoid-arthritis/