Junctional adhesion molecule-C is a soluble mediator of angiogenesis.
Junctional adhesion molecule-C (JAM-C) is an adhesion molecule expressed by endothelial cells (ECs) that plays a role in tight junction formation, leukocyte adhesion, and transendothelial migration. In the current study, we investigated whether JAM-C is found in soluble form and whether soluble JAM-C (sJAM-C) mediates angiogenesis. We found that JAM-C is present in soluble form in normal serum and elevated in rheumatoid arthritis (RA) serum. The concentration of sJAM-C is also elevated locally in RA synovial fluid compared with RA serum or osteoarthritis synovial fluid. sJAM-C was also present in the culture supernatant of human microvascular ECs (HMVECs) and immortalized human dermal microvascular ECs, and its concentration was increased following cytokine stimulation. In addition, sJAM-C cleavage from the cell surface was mediated in part by a disintegrin and metalloproteinases 10 and 17. In functional assays, sJAM-C was both chemotactic and chemokinetic for HMVECs and induced HMVEC tube formation on Matrigel in vitro. Neutralizing anti-JAM-C Abs inhibited RA synovial fluid-induced HMVEC chemotaxis and sJAM-C-induced HMVEC tube formation on Matrigel. sJAM-C also induced angiogenesis in vivo in the Matrigel plug and sponge granuloma models. Moreover, sJAM-C-mediated HMVEC chemotaxis was dependent on Src, p38, and PI3K. Our results show that JAM-C exists in soluble form and suggest that modulation of sJAM-C may provide a novel route for controlling pathological angiogenesis.
Rabquer
Bradley J
BJ
Department of Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. brabquer@umich.edu
Amin
Mohammad A
MA
Teegala
Nanditha
N
Shaheen
Matthew K
MK
Tsou
Pei-Suen
PS
Ruth
Jeffrey H
JH
Lesch
Charles A
CA
Imhof
Beat A
BA
Koch
Alisa E
AE
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000473:pathology / Q000628:therapy; D015815:Cell Adhesion Molecules / Q000097:blood / Q000502:physiology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007136:Immunoglobulins / Q000097:blood / Q000502:physiology* / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000097:blood / Q000502:physiology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000276:immunology*; D011956:Receptors, Cell Surface; D012995:Solubility; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism
D015815:Cell Adhesion Molecules; C407243:F11R protein, human; D007136:Immunoglobulins; D018836:Inflammation Mediators; D011956:Receptors, Cell Surface