The anti-allergic compound tranilast attenuates inflammation and inhibits bone destruction in collagen-induced arthritis in mice.
OBJECTIVE
Recent findings suggest the importance of mast cells in the pathogenesis of rheumatoid arthritis and their potential as a therapeutic target. Tranilast is an anti-allergic compound with a potent membrane-stabilizing effect on mast cells and a wide range of anti-inflammatory effects, thus may be advantageous in the treatment of arthritis. Here, we have evaluated the effects of tranilast on the progression of collagen-induced arthritis in mice.


METHODS
Tranilast (400 mg.kg(-1).day(-1)) was orally administered for 8 weeks to mice with established collagen-induced arthritis. Arthritis was assessed by clinical signs and X-ray scores. In paw tissue, the numbers of mast cells and osteoclasts were measured by histological analysis, and several inflammatory factors were assessed by RT-PCR and Western blot analysis.*


RESULTS
TNF-alpha-positive mast cells were present extensively throughout the inflamed synovium of vehicle-treated arthritic mice, with some mast cells in close proximity to osteoclasts in areas of marked bone and cartilage destruction. Tranilast significantly reduced clinical and X-ray scores of arthritis and decreased numbers of TNF-alpha-positive mast cells and mRNA levels of TNF-alpha, chymase (mouse mast cell protease 4), tryptase (mouse mast cell protease 6), stem cell factor, interleukin-6, cathepsin-K, receptor activator of nuclear factor-kappaB, and of receptor activator of nuclear factor-kappaB-ligand, but increased interleukin-10 mRNA level in paws of arthritic mice. Osteoclast numbers were decreased by treatment with tranilast.


CONCLUSIONS
Tranilast possesses significant anti-rheumatic efficacy and, probably, this therapeutic effect is partly mediated by inhibition of mast cell activation and osteoclastogenesis.
Shiota
N
N
Department of Pharmacology, Shimane University School of Medicine, Shimane, Japan. shiotana@med.shimane-u.ac.jp
Kovanen
P T
PT
Eklund
K K
KK
Shibata
N
N
Shimoura
K
K
Niibayashi
T
T
Shimbori
C
C
Okunishi
H
H
D000818:Animals; D018926:Anti-Allergic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009841:Oligonucleotides; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics / Q000494:pharmacology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D014965:X-Rays; D062367:ortho-Aminobenzoates
D018926:Anti-Allergic Agents; D002352:Carrier Proteins; D015850:Interleukin-6; D009841:Oligonucleotides; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; D062367:ortho-Aminobenzoates; C116746:phosphodiester alpha; D016753:Interleukin-10; C012293:tranilast