ONO-4817, an orally active matrix metalloproteinase inhibitor, prevents lipopolysaccharide-induced proteoglycan release from the joint cartilage in guinea pigs.
OBJECTIVE
To evaluate the effect of a newly developed inhibitor of matrix metalloproteinases (MMPs), ONO-4817, on the degradation of cartilage in the guinea pig arthritis model.


METHODS
42 guinea pigs were used in the arthritis model.


METHODS
Lipopolysaccharide (LPS) was injected into guinea pig knee joints. The content of proteoglycan released in synovial cavity was measured as a marker of cartilage degradation. ONO-4817, dexamethasone or indomethacin were administered orally to the animals.


RESULTS
ONO-4817 showed a broad inhibitory activity against MMPs except MMP-1 and MMP-7. The oral administration of ONO-4817 dose-dependently suppressed the release of proteoglycan from the cartilage of the knee joints.


CONCLUSIONS
This study suggests the possibility that a novel MMP inhibitor, ONO-4817 may have a therapeutic utility for MMP-related diseases.
Yamada
A
A
Discovery Research Laboratory II, Minase Research Institute, ONO Pharmaceutical Co., Ltd., Osaka, Japan.
Uegaki
A
A
Nakamura
T
T
Ogawa
K
K
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000378:metabolism*; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D010647:Phenyl Ethers / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D011480:Protease Inhibitors; D011509:Proteoglycans; D003907:Dexamethasone; D007213:Indomethacin