mdl-201053 and Arthritis

To elucidate the role of reactive oxygen species (ROS) in arthritis and to identify targets of arthritis treatment in conditions with different levels of oxidant stress.. Through establishing an arthritis model by injecting arthritogenic serum into wild-type and NADPH oxidase 2 (NOX2)-deficient mice, we found that arthritis had a neutrophilic infiltrate and was more severe in Ncf1(-/-) mice, a mouse strain lacking the expression of the NCF1/p47(phox) component of NOX2. The levels of interleukin-1β (IL-1β) and IL-6 in inflamed joints were higher in Ncf1(-/-) than in controls. Antagonists of tumor necrosis factor-α (TNFα) and IL-1β were equally effective in suppressing arthritis in wild-type mice, while IL-1β blockade was more effective than TNFα blockade in Ncf1(-/-) mice. A treatment of caspase inhibitor and the combination treatment of a caspase inhibitor and a cathepsin inhibitor, but not a cathepsin inhibitor alone, suppressed arthritic severity in the wild-type mice, while a treatment of cathepsin inhibitor and the combination treatment of a caspase inhibitor and a cathepsin inhibitor, but not a caspase inhibitor alone, were effective in treating Ncf1(-/-) mice. Consistently, cathepsin B was found to proteolytically process pro-IL-1β to its active form and this activity was suppressed by ROS.. This novel mechanism of a redox-mediated immune regulation of arthritis through leukocyte-produced ROS is important for devising an optimal treatment for patients with different levels of tissue ROS.. Our results suggest that ROS act as a negative feedback to constrain IL-1β-mediated inflammation, accounting for the more severe arthritis in the absence of NOX2.

Topics: Amino Acid Chloromethyl Ketones; Animals; Ankle Joint; Arthritis; Caspase Inhibitors; Cathepsin B; Cell Line; Cytokines; Dipeptides; Disease Models, Animal; Fibroblasts; Humans; Inflammation; Interleukin-1beta; Ketones; Lung; Membrane Glycoproteins; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; NADPH Oxidase 2; NADPH Oxidases; Oxidation-Reduction; Reactive Oxygen Species; Wrist Joint

The role of cathepsin B, H and L activities in arthritic processes was studied histochemically using specific synthetic substrates in a postcoupling method on unfixed and undecalcified cryostat sections of rat knee joints. Only cathepsin B in synoviocytes, chondrocytes and fibroblasts showed a strong increase in activity due to antigen induced arthritis. The addition of a tissue stabilizer, polyvinyl alcohol, to the incubation medium enabled us to demonstrate extracellular enzymic activity within the articular cartilage matrix of arthritic joints. Both intravenous and oral treatment of the animals with a selective inhibitor of cathepsin B, Z-Phe-Ala fluoromethyl ketone (CH2F), during the development of arthritis suppressed the degree of inflammation and resulted in decreased intracellular and extracellular cathepsin B activity as detected histochemically, and less cartilage damage. Our study indicates that (a) cathepsin B-like activity plays a role in the cascade of proteolytic cartilage destruction, (b) chondrocytes and fibroblasts may well be involved in the breakdown of cartilage and ligaments, and (c) Z-Phe-AlaCH2F could be of therapeutic value.

Topics: Administration, Oral; Animals; Arthritis; Arthritis, Experimental; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Dipeptides; Female; Histocytochemistry; Injections, Intravenous; Ketones; Knee Joint; Rats; Rats, Inbred Strains