Regular aticleThe role of COX-2 in angiogenesis and rheumatoid arthritis☆☆
Introduction
Neovascularization is a hallmark of rheumatoid arthritis (RA) synovial tissue (ST), likely driven by the increased demand for nutrients and oxygen required by the invasive and proliferative synovial pannus Folkman 1995, Koch 1998, Walsh 1999. Early RA synovium is characterized by an increase in sublining capillary and postcapillary venule density. The quantity of synovial blood vessels correlates with synovial cell hyperplasia, mononuclear cell number, and the Ritchie articular index of joint tenderness (Rooney et al., 1988). Studies in animal models provide optimism about the use of angiogenesis inhibitors for RA Brooks et al 1994, Oliver et al 1995, Storgard et al 1999, Kim et al 2002, Yin et al 2002. In short, angiogenesis appears to be a key event in the initiation and persistence of rheumatoid disease and can be strategically inhibited to reduce inflammation in animal models of RA.
Prior to the advent of distinct probes for COX isoforms, many joint cell types were shown to positively immunostain for COX (Sano et al., 1992). Joints from RA patients exhibited abundant COX expression, to higher levels than found in ST from osteoarthritis patients or nonarthritic ST (Sano et al., 1992). Later studies with human and animal tissues used specific COX antibodies and demonstrated COX-2 immunostaining of synovial blood vessels, synovial lining cells, chondrocytes, lymphoid aggregates, and subsynovial fibroblast-like cells Crofford et al 1994, Kang et al 1996, Siegle et al 1998. The advancement of specific COX-2 inhibitors to the clinic represents a major step forward in the pharmacologic approach to the treatment of arthritis. These specific inhibitors have been shown in clinical trials to relieve pain and inflammation associated with RA as effectively as nonsteroidal anti-inflammatory drugs with significantly less adverse side effects (Schnitzer and Hochberg, 2002).
Evidence from a variety of models demonstrates that COX-1 and/or COX-2 regulate angiogenesis or various facets of the angiogenic response Majima et al 1997, Katori et al 1998, Tsujii et al 1998, Daniel et al 1999, Hull et al 1999, Jones et al 1999, Sawaoka et al 1999, Yamada et al 1999, Dicker et al 2001, Hernandez et al 2001. The mechanism through which COX-2 promotes an angiogenic phenotype is likely related to the proangiogenic properties of select eicosanoids, including PGE2, PGE1, and TxA2 Form and Auerbach 1983, Diaz-Flores et al 1994, Nie et al 2000. The RA ST has been examined for eicosanoid production and the principal products of COX activity are PGE2, PGF2α, TxA2, and PGI2 (Goldstein, 1988). While evidence suggests that COX-2 modulates angiogenesis and COX-2 is upregulated in RA ST, it is not known whether the proangiogenic function of COX-2 contributes to the persistent vascularization in inflamed synovium. In addition, at the onset of these studies, it was not clear whether endothelial COX-2 directly played a role in in vitro angiogenesis. Therefore, we examined the role of COX-2 in RA synovial fibroblasts and microvascular ECs. Our results represent the first demonstration that COX-2 induced angiogenic activity is likely an active mechanism within diseased synovium and provides an additional rationale for the use of COX-2 inhibitors in RA.
Section snippets
Cells and generation of conditioned medium (CM)
Human dermal microvascular endothelial cells (HMVECs) were purchased from Cambrex Bio Science Walkersville (Walkersville, MD) and grown in endothelial cell growth medium (EGM, Cambrex Bio Science, Walkersville, MD) with 10% FBS. Cell assays were performed in endothelial basal medium (EBM, Cambrex Bio Science) supplemented as described below. Fibroblasts were isolated from fresh RA STs. Patients met the criteria established by the American College of Rheumatology (Arnett et al., 1988). All
Rofecoxib inhibits PMA-induced HMVEC chemotaxis
Coculture findings from an early study using human umbilical vein ECs (HUVECs) suggested that COX-1 but not COX-2 was important in regulating facets of angiogenesis (Tsujii et al., 1998). Results from a subsequent study performed using rat primary aortic ECs and HMVECs, however, suggested that EC COX-2 was of importance (Jones et al., 1999). In light of this discrepancy, we set out to directly analyze the effects of a specific COX-2 inhibitor on ECs involved in chemotaxis and tube formation. We
Acknowledgements
This work was supported by a grant from Merck & Company, Inc. (J.M.W. and A.E.K.), NIH grants AI-40987 and HL-58695 (A.E.K.), the Veterans’ Administration Research Service (A.E.K.), and the Gallagher Professorship for Arthritis Research (A.E.K.).
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Preliminary results were presented as part of the 66th National Meeting of the American College of Rheumatology.