Blockade of integrin VLA-4 prevents inflammation and matrix metalloproteinase expression in a murine model of accelerated collagen-induced arthritis.
DBA/1LacJ mice were immunized with type II collagen and boosted with bacterial lipopolysaccharide (LPS) 17 days later to induce accelerated arthritis. Clinical signs of inflammation were observed as early as Day 20. Matrix metalloproteinases MMP-2, -3, -9, and -13, but not MMP-12, mRNA levels were increased on Day 24. Administration of anti-VLA-4 antibody (mAb; 8 mg/kg/day for 3 days) at the time of LPS treatment strikingly inhibited arthritis-induced paw inflammation and histological scores, but not the increase in MMP expression. A higher dose of mAb (20 mg/kg/day for 4 days) inhibited pathology and normalized the levels of MMP mRNAs. In conclusion, the pathophysiology of this accelerated model of arthritis is VLA-4-dependent, and VLA-4-mediated events have a role in inflammation-induced MMP expression. Inhibition of arthritis-induced increases in MMP expression is not necessary to reduce pathology. This model is well suited for identifying agents that block integrin VLA-4 in vivo.
Raychaudhuri
Anil
A
Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
Chou
Mary
M
Weetall
Marla
M
Jeng
Arco Y
AY
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D001168:Arthritis / Q000139:chemically induced / Q000209:etiology / Q000473:pathology*; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000209:etiology* / Q000517:prevention & control; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000096:biosynthesis; D013997:Time Factors
D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003094:Collagen; D020782:Matrix Metalloproteinases