Collagen-induced arthritis in the DBA/1 mouse is an experimental model of human rheumatoid arthritis. To examine the role of leukotrienes in the pathogenesis of this disease, we have developed embryonic stem (ES) cells from this mouse strain. Here, we report that DBA/1 mice made deficient in 5-lipoxygenase-activating protein (FLAP) by gene targeting in ES cells develop and grow normally. Zymosan-stimulated leukotriene production in the peritoneal cavity of these mice is undetectable, whereas they produce substantial amounts of prostaglandins. The inflammatory response to zymosan is reduced in FLAP-deficient mice. The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals. This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice. These data demonstrate that leukotrienes play an essential role in both the acute and chronic inflammatory response in mice.

Microsomal prostaglandin E synthase (mPGES)-1 is one of several prostaglandin E synthases involved in prostaglandin H 2 (PGH2) metabolism. In the present report, we characterize the contribution of mPGES-1 to cellular PGH2 metabolism in murine macrophages by studying the synthesis of eicosanoids and expression of eicosanoid metabolism enzymes in wild type and mPGES-1-deficient macrophages. Thioglycollate-elicited macrophages isolated from mPGES-1؊/؊ animals and genetically matched wild type controls were stimulated with diverse pro-inflammatory stimuli. Prostaglandins were released in the following order of decreasing abundance from wild type macrophages stimulated with lipopolysaccharide: prostaglandin E 2 (PGE2) > thromboxane B 2 (TxB2) > 6-keto prostaglandin F 1␣ (PGF1␣), prostaglandin F 2␣ (PGF2␣), and prostaglandin D 2 (PGD2). In contrast, we detected in mPGES-1؊/؊ macrophages a >95% reduction in PGE2 production resulting in the following altered prostaglandin profile: TxB2 > 6-keto PGF1␣ and PGF2␣ > PGE2, despite the comparable release of total prostaglandins. No significant change in expression pattern of key prostaglandin-synthesizing enzymes was detected between the genotypes. We then further profiled genotype-related differences in the eicosanoid profile using macrophages pre-stimulated with lipopolysaccharide followed by a 10-min incubation with 10 M

Objective. It has been reported that osteoarthritis can occur in hamsters. The present study was undertaken to determine the effects of exercise on the composition of articular cartilage and synovial fluid and on the development of cartilage degeneration in these animals.Methods. Young (2.5-month-old) group-housed hamsters were compared with 5.5-month-old hamsters that had undergone 3 months of daily wheel running exercise (6-12 km/day) or 3 months of sedentary, individually housed living. The condition of the femoral condyles was determined by scanning electron microscopy in 12 exercising hamsters, 12 sedentary hamsters, and 6 of the young controls. The content of proteoglycan, hyaluronic acid, hydroxyproline, and proline in synovial fluid and patellar cartilage was measured.Results. By scanning electron microscopy, the femoral articular cartilage was smooth and undulating in young controls and older exercising hamsters. In contrast, the femoral condyles were fibrillated in all 12 of the sedentary hamsters. There was no difference in the patellar cartilage collagen content between the 3 groups, but proteoglycan content and synthesis were lower in the patellar cartilage of the sedentary group. Synovial fluid volume was also decreased in the sedentary group compared with the young controls or the older exercising hamsters.Conclusion. A sedentary lifestyle in the hamster leads to a lower proteoglycan content in the cartilage and a lower synovial fluid volume. These changes are associated with cartilage fibrillation, pitting, and fissur-

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