az-11645373 and Joint-Diseases

The ATP-gated P2X(7) receptor (P2X(7)R) is a promising therapeutic target in chronic inflammatory diseases with highly specific antagonists currently under clinical trials for rheumatoid arthritis. Anti-inflammatory actions of P2X(7)R antagonists are considered to result from inhibition of P2X(7)R-induced release of proinflammatory cytokines from activated macrophages. However, P2X(7)Rs are also expressed in resting macrophages, suggesting that P2X(7)R may also signal via cytokine-independent mechanisms involved in joint disease. In this study, we examined P2X(7)R function in resting human lung macrophages and mouse bone marrow-derived macrophages and found that ATP induced rapid release of the lysosomal cysteine proteases cathepsin B, K, L, and S and that was independent of the presence of the proinflammatory cytokines IL-1beta and IL-18. Cathepsins released into the medium were effective to degrade collagen extracellular matrix. ATP-induced cathepsin release was abolished by P2X(7)R antagonists, absent from P2X(7)R(-/-) mouse macrophages, and not associated with cell death. Our results suggest P2X(7)R activation may play a novel and direct role in tissue damage through release of cathepsins independently of its proinflammatory actions via IL-1 cytokines.

Topics: Adenosine Triphosphate; Animals; Blotting, Western; Cathepsin B; Cathepsins; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Etanercept; Humans; Immunoglobulin G; Immunosuppressive Agents; Interleukin-1beta; Joint Diseases; L Cells; Macrophages; Methotrexate; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2X7; Receptors, Tumor Necrosis Factor; Thiazoles