Blockade of Vascular Endothelial Growth Factor Receptor I (VEGF-RI), but not VEGF-RII, Suppresses Joint Destruction in the K/BxN Model of Rheumatoid Arthritis

Abstract

It was recently shown that vascular endothelial growth factor (VEGF), a growth factor for endothelial cells, plays a pivotal role in rheumatoid arthritis. VEGF binds to specific receptors, known as VEGF-RI and VEGF-RII. We assessed the physical and histological effects of selective blockade of VEGF and its receptors in transgenic K/BxN mice, a model of rheumatoid arthritis very close to the human disease. Mice were treated with anti-mouse VEGF Ab, anti-mouse VEGF-RI and -RII Abs, and an inhibitor of VEGF-RI tyrosine kinase. Disease activity was monitored using clinical indexes and by histological examination. We found that synovial cells from arthritic joints express VEGF, VEGF-RI, and VEGF-RII. Treatment with anti-VEGF-RI strongly attenuated the disease throughout the study period, while anti-VEGF only transiently delayed disease onset. Treatment with anti-VEGF-RII had no effect. Anti-VEGF-RI reduced the intensity of clinical manifestations and, based on qualitative and semiquantitative histological analyses, prevented joint damage. Treatment with a VEGF-RI tyrosine kinase inhibitor almost abolished the disease. These results show that VEGF is a key factor in pannus development, acting through the VEGF-RI pathway. The observation that in vivo administration of specific inhibitors targeting the VEGF-RI pathway suppressed arthritis and prevented bone destruction opens up new possibilities for the treatment of rheumatoid arthritis.

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

“…Other receptors involved in angiogenesis, such as Tie receptors and their ligands, the angiopoietins, are known to be expressed in synovial membrane from RA patients and are regulated by TNF␣ (27). In addition, it is known that soluble chimeric VEGFR-1 protein abrogates angiogenesis in RA (28), while blockade of VEGFR-1, but not VEGFR-2, was shown to be beneficial in a transgenic mouse model of RA (29). Matrix metalloproteinases such as ADAMS have been found to be involved directly in the cleavage of extra (8).…”

Potential role of heme oxygenase-1 in the progression of rat adjuvant arthritis

“…51 It is believed that VEGF plays a central role in pannus development and thus administration of specific inhibitors of the VEGF-RI pathway suppresses arthritis and prevents bone destruction in experimental arthritis. 52 It has been demonstrated that HO-1 activity can be related to angiogenesis. Thus, this enzyme has been shown to induce VEGF in cultured endothelial cells by an increased transcription likely dependent on CO generated by HO-1 activity.…”

Therapeutic effect of anti-vascular endothelial growth factor receptor I antibody in the established collagen-induced arthritis mouse model

“…Vascular endothelial growth factor (VEGF), the most powerful angiogenic molecule, is associated with various physiological and pathological neovascularization, including synovial angiogenesis in RA [3]. In RA, VEGF is strongly expressed by synovial macrophages, fibroblasts surrounding microvessels, vascular smooth muscle cells, and synovial lining cells [4,5]. VEGF expression begins very early and it also persists throughout the disease course [4,5].…”

“…In RA, VEGF is strongly expressed by synovial macrophages, fibroblasts surrounding microvessels, vascular smooth muscle cells, and synovial lining cells [4,5]. VEGF expression begins very early and it also persists throughout the disease course [4,5]. VEGF binds two types of receptors: vascular endothelial growth factor receptor I (VEGF RI) and vascular endothelial growth factor receptor II (VEGF RII) [6].…”

“…VEGF binds two types of receptors: vascular endothelial growth factor receptor I (VEGF RI) and vascular endothelial growth factor receptor II (VEGF RII) [6]. Both VEGF RI and VEGF RII are expressed on the cell surface of synovial cells and blood endothelial cells, and VEGF RII is the major mediator of endothelial cell mitogenesis and survival, as well as angiogenesis and microvascular permeability [4,6]. However, in the collagen-induced arthritis (CIA) mice model and KRN/NOD (K/BxN) transgenic mice model, anti-VEGF RII treatment had no effects on preventingLutten A et al [7] showed that endothelial cells of synovial microvessels have high levels of tyrosine kinase receptor VEGF RI messenger RNA.…”