Abstract
ABSTRACTChronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted 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 blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA. We determined CatWalk-assisted gait profiles as objective quantitative measurements of functional impairment. We first determined body-weight-independent gait parameters, including maximum intensity, print length, print width and print area in wild-type mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 – the first clinical signs of arthritis. Moreover, we found further gait changes during chronic disease development, indicating progressive functional impairment in hTNFtg mice. By investigating the association of gait parameters with inflammation-mediated joint pathologies at different time points of the disease course, we found a relationship between gait parameters and 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 blocking TNF, even at progressed stages of disease. However, blocking TNF did not restore full functionality owing to remaining subclinical inflammation and structural microdamage. 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.
Highlights
Rheumatoid arthritis (RA) is a systemic and chronic inflammatory autoimmune disease characterized by synovial inflammation induction of cartilage and bone destruction
We found that static parameters such as print length, print width and maximum contact area are independent of body weight and age and, offer useful quantitative gait parameters to assess longitudinal gait changes and functional disabilities in human-TNF transgenic (hTNFtg) mice affected by chronic inflammatory erosive arthritis
After the treatment period of 5 weeks, we observed significant increases in gait parameters, including maximum intensity, mean intensity and print width in hTNFtg animals that had been treated with a tumor necrosis factor (TNF) blocker compared to hTNFtg mice that had been treated with a placebo (Fig. 4C)
Summary
Rheumatoid arthritis (RA) is a systemic and chronic inflammatory autoimmune disease characterized by synovial inflammation induction of cartilage and bone destruction. Chronic arthritis in turn leads to functional impairment and loss of mobility in affected individuals, which dramatically reduces their quality of life. Recent studies in RA individuals demonstrate that even successful treatment with complete resolution of synovial inflammatory processes does not lead to a complete reversibility of joint functionality (Aletaha et al, 2006). This finding points to the crucial contribution of irreversibly damaged structural components, such as bone or cartilage, to reduced joint mobility
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