Abstract
IntroductionThe translational and predictive value of animal models highly depends on the validity of respective readout parameters. In arthritis research, there has been a shift from sole threshold testing for pain-related behavior, as well as from swelling and histology assessment for inflammation, toward an analysis of joint function as indicated, for instance, by an increasing number of studies on gait abnormalities. Clinically, the range of motion (ROM) of the affected joint plays a major role in diagnosis and the assessment of treatment benefits. This parameter, however, is only insufficiently detected by currently used analytic systems in animals.MethodsHere we used high-resolution videoradiographic analysis to assess ROM in experimental knee joint arthritis in rats. This parameter is described during the 21-day course of antigen-induced arthritis in rats. Furthermore, the therapeutic effects of antinociceptive (morphine) and anti-inflammatory (dexamethasone) treatment on ROM are documented. To obtain additional information on the implications of ROM in animal models, correlations were performed to measure pain-related behavior and inflammation.ResultsThe study animals showed a significant reduction in ROM of the inflamed knee joint in the acute phase of arthritis. This was accompanied by an increase in knee joint movement on the contralateral side, indicating a compensational mechanism. Both morphine and dexamethasone treatment increased and thus normalized ROM. Changes in ROM were further stage-dependently correlated with weight bearing and joint swelling, that is, with both pain-related behavior and signs of inflammation.ConclusionsThe dynamic ROM observed in freely moving rats in our model of knee joint arthritis might serve as a parameter for global disease activity and might thus represent a promising readout parameter for preclinical assessment regarding the overall efficacy not only of antiarthritic but also of antinociceptive compounds.
Highlights
The translational and predictive value of animal models highly depends on the validity of respective readout parameters
The study animals showed a significant reduction in range of motion (ROM) of the inflamed knee joint in the acute phase of arthritis
All 30 animals in which intraarticular methylated bovine serum albumin (mBSA) injections were performed developed signs of antigen-induced arthritis (AIA), including swelling, pain-related behavior and histopathological changes assessed on day 21, and they were included in the analysis
Summary
The translational and predictive value of animal models highly depends on the validity of respective readout parameters. One major problem in preclinical arthritis research is a reliable assessment of symptom severity and its alleviation by standard of care medication in respective animal models to achieve a good translational potency for predicting clinical outcome. In recent years, it has become more and more obvious that in addition to, for instance, pain threshold detection or assessment of joint swelling [2], functional parameters have great potential to identify arthritis-related surrogate parameters in animals. Parameters assessed include the speed of walking, spatial and temporal measures of step cycles (distances between pawprints, stance time, swing time and so on), the pressure and area of the pawprints and rotation in the respective limb [3,4,5,6,7,8]
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