Prevention of progressive joint destruction in collagen-induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031.
FR255031 (2-[(7S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxido-4-(2-pyridinylcarbonyl)hexahydro-1,4-thiazepin-7-yl]-N-hydroxyacetamide) is a novel synthetic matrix metalloproteinase (MMP) inhibitor that inhibits human collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9) and membrane type 1 MMP (MT1-MMP/MMP-14). FR255031 also inhibits rat collagenase and gelatinase. We studied the effect of FR255031 and Trocade, an inhibitor of collagenase and MMP-14, on a rat collagen-induced arthritis (CIA) model. Rat CIA was induced by intradermal injection of type II collagen (IIC) and oral administration of FR255031 or Trocade was performed for 28 days. Body weight loss, hind paw swelling, elevation of serum anti-IIC antibody, and histological and radiographic scores were evaluated. FR255031 markedly inhibited cartilage degradation in a dose-dependent manner in the CIA model, but Trocade failed to prevent the degradation. FR255031 at a dose of 100 mg kg(-1) also had statistically significant effects on bone destruction and pannus formation and on the recovery of body weight loss on day 28. These results indicate that FR255031 is effective for rat CIA, especially on joint cartilage destruction. These data suggest that as well as collagenases or MT-MMP, gelatinases are also involved in joint destruction in arthritis.
Ishikawa
Takeshi
T
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. takeshi_ishikawa@po.fujisawa.co.jp
Nishigaki
Fusako
F
Miyata
Susumu
S
Hirayama
Yoshitaka
Y
Minoura
Kyoko
K
Imanishi
Junko
J
Neya
Masahiro
M
Mizutani
Tsuyoshi
T
Imamura
Yoshimasa
Y
Naritomi
Yoichi
Y
Murai
Hidetsugu
H
Ohkubo
Yoshitaka
Y
Kagayama
Akira
A
Mutoh
Seitaro
S
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000473:pathology / Q000517:prevention & control; D005260:Female; D006614:Hindlimb / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D007592:Joint Diseases / Q000517:prevention & control*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D015394:Molecular Structure; D011859:Radiography; D051381:Rats; D011917:Rats, Inbred Lew; D013841:Thiazepines / Q000494:pharmacology*
C501459:FR255031; D061965:Matrix Metalloproteinase Inhibitors; D013841:Thiazepines; D020782:Matrix Metalloproteinases