Hepatocyte growth factor. A cytokine mediating endothelial migration in inflammatory arthritis

Abstract

Objective. Angiogenesis is an integral component of the vasculoproliferative phase of rheumatoid arthritis (RA). Recently, a heparin‐binding cytokine termed hepatocyte growth factor (HGF), or scatter factor (due to its ability to disperse cohesive epithelial colonies), was described. We conducted this study to investigate the hypothesis that this cytokine was present in the milieu of the inflamed joint, and that it contributed to the chemotaxis of endothelial cells in the synovial tissue. Methods. We examined synovial fluid, synovial tissue, and peripheral blood from 91 patients with RA and other arthritides. We used 83 total samples in an enzyme‐linked immunosorbent assay to quantitate the HGF in synovial fluids and peripheral blood. To determine whether the HGF was biologically active, an epithelial scatter factor assay was performed. Immunohistochemical analysis was used to determine localization in synovial tissues. To define a function for synovial HGF, we preincubated rheumatoid synovial fluids with neutralizing anti‐HGF and measured the ability of these synovial fluids to induce endothelial chemotaxis. Results. Synovial fluid from patients with RA contained a mean ± SEM HGF concentration of 2.0 ± 0.3 ng/ml, while synovial fluid from patients with other arthritides (including inflammatory arthritis) contained 2.4 ± 0.7 ng/ml HGF. Osteoarthritis (OA) patient samples contained the smallest quantities of synovial fluid HGF at 0.9 ± 0.1 ng/ml. RA synovial fluid contained significantly more HGF than did RA peripheral blood (1.1 ± 0.2 ng/ml) (P < 0.05). Rheumatoid synovial fluids induced more scattering of cells than did OA synovial fluids, suggesting a role for this cytokine in rheumatoid joint destruction. Interleukin‐1β induced expression of rheumatoid synovial tissue fibroblast antigenic HGF and scatter factor activity. Immunohistochemically, HGF, as well as the HGF receptor (the met gene product), localized to significantly more rheumatoid synovial tissue lining cells than normal lining cells (P < 0.05). Both HGF and its receptor immunolocalized to subsynovial macrophages as well. Levels of synovial tissue immunoreactive HGF correlated positively with the number of synovial tissue blood vessels. Anti‐HGF neutralized a mean of 24% of the chemotactic activity for endothelial cells found in 10 rheumatoid synovial fluid samples. Conclusion. These results indicate that synovial HGF may contribute to the vasculoproliferative phase of inflammatory arthritides such as RA, by inducing HGF‐mediated synovial neovascularization. These findings point to a newly described role for HGF in the fibroproliferative phase of RA‐associated synovitis.

Dickkopf-1 Is Associated with Periarticular Bone Loss in Patients with Rheumatoid Arthritis*

“…Although we and others have shown that HGF inhibits osteoblast differentiation [6,7] it seems clear that the effect of HGF on osteoblast differentiation is dependent on the concentration of the cytokine, and that HGF at low concentrations in fact may promote rather than inhibit osteoblastogenesis [14]. Plasma levels of HGF correlate to levels of HGF in synovial fluid, and levels of HGF are higher in synovial fluid than in serum obtained simultaneously from the same individuals [15,16]. Hence, HGF at high concentrations in the joints are more likely to act negatively on osteoblasts than HGF at the lower concentrations found in circulation.…”

Vascular endothelial growth factor mRNA and protein expression in airway epithelial cell linesin vitro

“…At the same time in other studies [7,8], a protein selectively mitogenic for vascular endothelial cells was purified from cell culture, and this protein turned out to be the same substance that induces vascular permeability-enhancing activity. VEGF is chemotactic for endothelial cells [9] and enhances their collagenase [10] and urokinase receptor expression [11]. The existence of multiple activities embodied in the same protein suggests that VEGF may play multifunctional roles both in the development of vasculature and in the maintenance of vascular structure and function.…”

Role of Bone Marrow in the Pathogenesis of Rheumatoid Arthritis

“…Of note, we have disclosed that the expression of VEGFR-2/KDR mRNA in RA bone marrow CD34+ cells was significantly higher than that in OA bone marrow CD34+ cells (Hirohata & Yanagida et al,2004). It is therefore likely that the differences in VEGF/KDR vascular activation in bone marrow CD34+ cells might result in differences in their capacity to generate endothelial progenitor cells between RA and OA patients (Koch et al,1994;Giatromanolaki et al,2001). It has been shown that decreased numbers and impaired function of endothelial progenitor cells (EPCs) resulting in defective vasculogenesis are associated with RA, leading to premature atherosclerosis (Herbrig et al, 2006;Pakozdi et al, 2009).…”