Article Text

PDF
SP0177 Inhibitory Pathways of Synovial Angiogenesis
  1. E. Brahn,
  2. on behalf of Cell-Cell Interaction in Joint Inflammation
  1. Division of Rheumatology, UCLA School of Medicine, Los Angeles, United States

Abstract

Introduction Angiogenesis occurs in a variety of normal processes, such as wound healing, organ development and the menstrual cycle. However, angiogenesis is also associated with numerous disease processes, including tumor growth, proliferative retinopathy, atherosclerosis and proliferative synovitis. Consequently, these pathologic processes are attractive therapeutic targets. Healthy joint vasculature is maintained by an appropriate balance between proangiogenic and antiangiogenic molecules. However, in rheumatoid arthritis (RA), this balance is disrupted; the levels of VEGF, hypoxia-inducible factor (HIF) and basic FGF (b-FGF), all of which are proangiogenic, are elevated in the joints of both patients with RA and in adjuvant-induced arthritis. The elevation of these proangiogenic factors occurs in the absence of adequate counterbalancing antiangiogenic factors. The new vasculature permits synovial hyperplasia which ultimately contributes to joint inflammation and structural damage.

Results In the United States, there are already at least 13 FDA approved anti-cancer therapies with recognized antiangiogenic properties in oncology that target the endothelial cell, pericyte, or tumor cell. These agents, which interrupt critical cell signaling pathways involved in tumor angiogenesis and growth, comprise three primary categories: 1) Monoclonal antibodies directed against specific proangiogenic growth factors and/or their receptors; 2) Small molecule tyrosine kinase inhibitors (TKIs) of multiple proangiogenic growth factor receptors; and 3) Inhibitors of mTOR (mammalian target of rapamycin). In addition there are other angiogenic agents whose mechanisms are not completely understood. A variety of angiogenesis inhibitors are being examined for their potential in treating RA, and although none of these compounds have advanced beyond phase II clinical trials, several angiogenesis inhibitors have demonstrated efficacy in preclinical RA models.

Conclusions Angiogenesis is an attractive therapeutic target although blood vessel growth is complex with multiple mechanisms. Different diseases may utilize different dominant pathways but surrogate markers such as bFGF, VEGF, and vessel density, may be helpful as predictors of likely candidates for therapeutic intervention. Angiogenesis inhibitors warrant further studies in rheumatic diseases. They lend themselves to combination therapies 1) that target multiple vessel proangiogenic pathways or 2) that could be used with biologic response modifiers.

Disclosure of Interest None declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.