Increased lymphangiogenesis in joints of mice with inflammatory arthritis.
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-kappaB) binding to an NF-kappaB 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-kappaB, leading to significantly increased lymphangiogenesis in joints of arthritic mice. The lymphatic system may play an important role in the pathogenesis of inflammatory arthritis.
Zhang
Qian
Q
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. qian_zhang@urmc.rochester.edu
Lu
Yan
Y
Proulx
Steven T
ST
Guo
Ruolin
R
Yao
Zhenqiang
Z
Schwarz
Edward M
EM
Boyce
Brendan F
BF
Xing
Lianping
L
D053687:Adult Stem Cells / Q000473:pathology / Q000502:physiology; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D007249:Inflammation / Q000473:pathology; D007596:Joints / Q000473:pathology; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse