Osteoimmunological Interactions at the Switch from Acute to Chronic Arthritis

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Rheumatoid arthritis is characterised by inflammation, cartilage destruction, and bone erosion. The pathogenic tissue response to inflammatory stimuli is of paramount importance for arthritis pathogenesis. Still, key events in the pathogenesis are not understood. One such unknown key event is the transition from acute to chronic inflammation, and the resistance of chronic inflammation to endogenous mechanisms of regulation and therapeutic suppression. We have found in a mouse model of arthritis that transient early depletion of regulatory T helper lymphocytes switches the usually acute, self-limiting course of arthritis to nonremitting, destructive arthritis. The critical switch in pathogenesis occurs early, in the preclinical phase of arthritis. We now want to use this system, in which arthritis can be switched ad libitum from acute, self limiting, to non-remitting, destructive, to identify the relevant molecular switches for the transition to chronic arthritis. Preliminary data suggest that T helper lymphocytes instruct synovial fibroblasts and osteoclasts to become the drivers of non-remitting destructive arthritis. We aim at defining the instructive signals from pathogenic T-lymphocytes; identify and characterise the molecular alterations in the effector cells responsible for non-remitting destructive arthritis; and find ways to modulate them.