Objective. To evaluate the effects of the phospholipase A, (PLA,) inhibitor manoalide on cartilage degradation, stromelysin expression, and inflammatory cell accumulation in rabbits treated intraarticularly with recombinant human interleukin-la (rHuIGla).Methods. Rabbits were given an intraarticular injettion of rHuIL-la. At various time points over a 24-hour period, the rabbits were euthanized and the articular space was lavaged with sterile PBS. The proteoglycan content of the lavage fluid was measured using a dimethylmethylene blue assay. PLA, activity and differential cell counts were also measured. The femur was removed and cartilage proteoglycan content determined. In some experiments, levels of synovial stromelysin messenger RNA (mRNA) were assessed. Manoalide or vehicle was administered 30 minutes before the rHuIL-la injection.Results. The rHuIL-la-induced arthritic response is characterized by significant accumulation of inflammatory cells, loss of proteoglycan from the condylar cartilage, and induction of mRNA for stromelysin. PLA, activity was also elevated in synovial fluids from rhIL-la-injected joints. Pretreatment with manoalide (0.3 mg/joint) significantly inhibited PLAz activity in the sflovial fluid, prevented the loss of proteoglycan from the condylar cartilage, and reduced proteoglycan levels in lavage fluids. However, manoalide either had no effect on, or stimulated, cell accumulation. To assess the
48105.Submitted for publication August 9, 1995; accepted in revised form March 13. 1996. relationship between the induction of PLA, and stromelysin, levels of stromelysin mRNA were measured in synovial tissue from manoalide-and vehicle-treated joints. Stromelysin message levels were significantly suppressed in a dose-dependent manner.Conclusion. These studies demonstrate that manoalide is a potent inhibitor of inflammation and cartilage catabolism, and suggest that PLA, is involved in the pathophysiology of rHuIL-la-induced arthritis in rabbits.The release of proteoglycan fragments from articular cartilage is an important feature of both rheumatoid arthritis (RA) and osteoarthritis. The cartilage proteoglycan matrix gives elasticity and resilience to cartilage, allowing the distribution of mechanical forces across the weight-bearing joint. The synovium releases a variety of mediators including interleukin-1 (IL-1) that stimulate chondrocytes to degrade extracellular proteoglycan, and extensive evidence suggests that IL-1 is involved in the pathology of chronic inflammatory arthritis. These studies have shown that IL-1 levels are elevated in synovial fluid from arthritis patients (1-4), messenger RNA (mRNA) for IL-1 is expressed at increased levels in RA synovial cells (5), IL-1 induces chondrocyte production of matrix metalloproteinases, including stromelysin and collagenase ( 6 -4 , IL-1 depresses proteoglycan biosynthesis by articular chondrocytes (9,10), and intraarticular injection of IL-la or IL-lP into rabbits induces an arthritic response that includes cellular infiltration and proteoglyc...
