Preservation of cartilage and bone architecture is the most important aspect for maintaining functionality in longstanding experimental arthritis

Abstract

Chronic inflammation of articular joints causing bone and cartilage destructions consequently leads to functional impairment or loss of mobility in affected joints from patients with Rheumatoid Arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes did not lead to full reversibility of joint functionality pointing to the crucial contribution of irreversibly damaged structural compartments such as bone or cartilage destruction on joint mobility. In this context, we investigated the impact of the distinct components including synovial inflammation, bone erosion or cartilage damage as well as the effect of a TNF blockade on functional impairment in human tumor necrosis factor transgenic (hTNFtg) mice, a chronic inflammatory, erosive animal model of Rheumatoid Arthritis (RA). We performed CatWalk-assisted gait profiles as objective, quantitative measurements indicating functional impairment. We first determined body weight independent gait parameters including maximum intensity, print length, print width and print area in wt mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 showing first clinical signs of arthritis. Moreover, we found further gait changes at chronic disease indicating progressive functional impairment in hTNFtg mice. By addressing associations of gait parameters with inflammation-mediated joint pathologies at different time points of the disease, we found a relationship of gait parameters with the extent of cartilage damage and bone erosions, but not with the extent of synovitis in this chronic model. Next, we observed a significant improvement of functional impairment upon TNF blockade even at progressed stage of disease. However, TNF blockade did not achieve full functionality due to remaining subclinical inflammation and structural microdamages. In conclusion, CatWalk gait analysis provides a useful tool for quantitative assessment of functional impairment in inflammatory, destructive arthritis. Our findings indicate that cartilage damage and bone erosion but not synovial inflammation are the most important determinants for progressive functional impairment in this chronic, erosive arthritis model.