INHIBITION OF CARTILAGE AND BONE DESTRUCTION IN ADJUVANT ARTHRITIS INTHE RAT BY A MATRIX METALLOPROTEINASE INHIBITOR

Considerable evidence has associated the expression of matrix metallop roteinases (MMPs) with the degradation of cartilage and bone in chroni c conditions such as arthritis. Direct evaluation of MMPs' role in viv o has awaited the development of MMP inhibitors with appropriate pharm acological properties. We have identified butanediamide, propyl)-N1-[2 -[[2-(morpholinyl)ethyl]-,[S-(R,S*)] (GI168) as a potent MMP inhibito r with sufficient solubility and stability to permit evaluation in an experimental model of chronic destructive arthritis (adjuvant-induced arthritis) in rats. In this model, pronounced acute and chronic synovi al inflammation, distal tibia and metatarsal marrow hyperplasia associ ated with osteoclasia, severe bone and cartilage destruction, and ecto pic new bone growth are well developed by 3 wk after adjuvant injectio n. Rats were injected with Freund's adjuvant on day 0. GI168 was was a dministered systemically from days 8 to 21 by osmotic minipumps implan ted subcutaneously. GI168 at 6, 12, and 25 mg/kg per d reduced ankle s welling in a dose-related fashion. Radiological and histological ankle joint evaluation on day 22 revealed a profound dose related inhibitio n of bone and cartilage destruction in treated rats relative to rats r eceiving vehicle alone. A significant reduction in edema, pannus forma tion, periosteal new bone growth and the numbers of adherent marrow os teoclasts was also noted. However no significant decrease in polymorph onuclear and mononuclear leukocyte infiltration of synovium and marrow hematopoietic cellularity was seen. This unique profile of antiarthri tic activity indicates that GI168 is osteo- and chondro-protective, an d it supports a direct role for MMP in cartilage and bone damage and p annus formation in adjuvant-induced arthritis.