Suppression of adjuvant arthritis of rats by a novel matrix metalloproteinase-inhibitor.
BAY 12-9566 (4-[4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) is a newly developed, synthetic matrix metalloproteinase (MMP) inhibitor (MMPI) that selectively inhibits MMP-2, MMP-3 and MMP-9 isozymes. We study the effect of BAY 12-9566 on inflammation and cartilage destruction in adjuvant-induced arthritis (AA) in rats. Rats were injected with adjuvant and treated for 21 days with vehicle, Indomethacin or BAY 12-9566. AA was assessed: by measuring arthritic index, paw volume, urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr); by examining joint inflammation; and by microscopic morphometry of articular cartilages. Oral treatment of rats for 22 days with 50 mg kg(-1) body weight/d BAY 12-9566 showed decreased AA as determined by improvement in body weight gain (P<0.01), arthritic index (P<0.05) and swelling of paws contralateral to the adjuvant injection site (P<0.05). Neutrophil infiltration and collagen degradation were also significantly lower (P<0.01) in this treatment group. Cartilage destruction was successfully suppressed (P<0.01) in rats treated with either 50 mg kg(-1) body weight/d BAY 12-9566 or 1 mg kg(-1) body weight/d Indomethacin. These results indicate that BAY 12-9566 successfully suppressed inflammation and cartilage destruction in rats with AA. Moreover, these results also suggested that MMP-2, MMP-3 and MMP-9 are involved in arthritic diseases such as rheumatoid arthritis.
Hamada
T
T
Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
Arima
N
N
Shindo
M
M
Sugama
K
K
Sasaguri
Y
Y
D000596:Amino Acids / Q000187:drug effects / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D001713:Biphenyl Compounds; D001835:Body Weight / Q000187:drug effects; D004487:Edema / Q000473:pathology / Q000517:prevention & control; D006614:Hindlimb; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010654:Phenylbutyrates; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects
D000596:Amino Acids; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010654:Phenylbutyrates; C015484:pyridinoline; C036020:deoxypyridinoline; C113281:Bay 12-9566; D007213:Indomethacin