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- Open Access
Tumor necrosis factor alpha modulates fibroblast-like synoviocyte expression of lymphangiogenesis-associated vascular endothelial growth factor C
© The Author(s) 2004
- Published: 13 September 2004
- Rheumatoid Arthritis
- Vascular Endothelial Growth Factor
- Tumor Necrosis Factor Alpha
- Synovial Tissue
- Protein Lysate
Vascular endothelial growth factor C (VEGF-C) is a member of the platelet-derived growth factor/vascular endothelial growth factor family of growth factors. Functionally, VEGF-C has been characterized as both a lymphangiogenic and angiogenic factor and can induce chemotaxis of macrophages. The exact mechanism by which the angiogenic, lymphangiogenic and cell recruitment processes are induced and maintained in the rheumatoid synovium of patients with rheumatoid arthritis (RA) is currently not known. We hypothesized that VEGF-C may be involved in RA and in this study proceeded to characterize its regulation in synoviocytes and tissue from RA and osteoarthritis (OA) patients.
Protein lysates were prepared from synovial tissue isolated from seven RA and six OA patients undergoing arthroplasty. Fibroblast-like synoviocytes (FLS) were grown out of synovial tissue samples and used at passages 2–5. Western blotting was employed to examine the VEGF-C isoforms. RT-PCR was used to examine VEGF-C receptors.
Western blots revealed an increase in the processed forms of VEGF-C in protein lysates prepared from synovial tissue of RA compared with OA patients. FLS produced substantial amounts of VEGF-C, the majority of which was secreted as the partially processed 29-kDa and 31-kDa forms that have been reported to bind to the lymphangiogenesis-associated VEGFR-3. These secreted forms were increased about 1.6-fold (P = 0.02) in RA FLS compared with OA FLS. The addition of 10 μg/ml tumor necrosis factor alpha (TNF-α) to the culture media increased the secreted VEGF-C forms an average of 1.4-fold in RA lines and 1.9-fold (P = 0.002) in OA lines. Additionally, mRNA levels for neuropilin-2, a receptor for VEGF-C and class 3 semaphorins that has been shown to be necessary for the formation of small lymphatic capillaries, were increased approximately 20-fold in both OA and RA lines 24 hours after TNF-α addition.
This is the first study to demonstrate that TNF-α-driven FLS may modulate synovial inflammation and joint destruction by paracrine and/or autocrine mechanisms involved in lymphangiogenesis.