Abstract
Angiogenesis is involved in the pathogenesis of inflammatory arthritis, but little is known about the role of lymphangiogenesis in this setting. Here, we examined whether tumor necrosis factor (TNF) stimulates osteoclast precursors (OCPs) to produce the lymphatic growth factor, vascular endothelial growth factor-C (VEGF-C), and induce lymphangiogenesis. We used TNF-transgenic (Tg) mice and mice with serum-induced arthritis. OCPs were purified by fluorescence-activated cell sorting of CD11b+/Gr-1-/lo blood or bone marrow cells and subjected to microarray analysis or were generated from spleen or joint cells and treated with TNF. Expression of VEGFs was analyzed and examined by real-time reverse transcription-polymerase chain reaction and Western blotting. Immunostaining and magnetic resonance imaging were used to quantify lymphatic vessels and volumes of synovium and draining lymph nodes. TNF stimulated VEGF-C expression by OCPs and increased nuclear factor-kappa B (NF-κB) binding to an NF-κB sequence in the VEGF-C promoter. OCPs from joints of TNF-Tg mice express high levels of VEGF-C. Lymphatic vessel numbers and size were markedly increased in joint sections of TNF-Tg mice and mice with serum-induced arthritis. The severity of synovitis correlated with draining lymph node size. In summary, TNF induces OCPs to produce VEGF-C through NF-κB, leading to significantly increased lymphangiogenesis in joints of arthritic mice. The lymphatic system may play an important role in the pathogenesis of inflammatory arthritis.
Highlights
Joint disease in rheumatoid arthritis (RA) is characterized by inflamed hyperplastic synovial tissue or 'pannus' formation [1]
vascular endothelial growth factor-C (VEGF-C) expression is upregulated in CD11b+/Gr-1-/lo osteoclast precursors from tumor necrosis factortransgenic mice Previous studies demonstrated an increase in circulating OCPs in patients [32] and animals [20] with arthritis and that OCP frequency is reduced in response to anti-TNF therapy, suggesting that OCPs may play important roles in the pathogenesis of arthritis [33]
To screen for novel genes that are differentially expressed by OCPs between arthritic and normal mice, we performed microarrays on RNA isolated from CD11b+/Gr-1-/lo OCPs from peripheral blood mononuclear cells and bone marrow pooled from tumor necrosis factor-transgenic (TNF-Tg) and WT mice
Summary
Joint disease in rheumatoid arthritis (RA) is characterized by inflamed hyperplastic synovial tissue or 'pannus' formation [1]. Pannus is composed of various cell types that produce a vast array of inflammatory mediators, including cytokines and chemokines that destroy the extracellular matrix in the joint by direct and indirect mechanisms. Inhibition of new blood vessel formation has been proposed as an important therapeutic approach for patients with inflammatoryerosive arthritis [3]. The lymphatic circulation has been known for many years to be an important secondary vascular system to remove fluid, macromolecules, and cells from the interstitial spaces, and it functions as a 'compensatory' system for blood circulation. Gene array analysis comparing lymphatic endothelial cells and blood vascular endothelial cells has recently identified numerous previously unknown lineage-spe-
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