Exercise Tolerance: A Novel Distress Free Model to Assess Osteoarthritis in Mice

Purpose: Osteoarthritis is a debilitating degenerative joint affecting over 80% of the human population above age 75 years. Unfortunately, there is no gold standard model to study osteoarthritis in experimental animals; hindering the understanding of the pathology and limiting the development of new treatments. Most behavioural tests measure indirectly knee joint pain rather than function. We developed a novel, non invasive technique to assess the progression of osteoarthritis in mice which examines the function of the knee joint in terms of the ability to exercise under both forced and voluntary conditions consistent with the fact that immobility is the most debilitating aspect of osteoarthritis in patients. Method: To induce osteoarthritis, C57Bl/6 mice were injected intra-articularly with monoiodoacetate (MIA); the control group received saline.  On day 1, 3, 8 and 22 post-injection, the ability to exercise under forced and voluntary conditions were determined and compared to the commonly used limping score and mechanical pain sensitivity using von Frey filaments.  Forced exercise ability was determined as the number of stumbles and slips occurring while running in motorized wheel system at a low speed.  Voluntary exercise ability was measured (using modified bicycle odometers) as the time spent running on individual voluntary exercise wheels over night.  Results:  MIA treated mice demonstrated decreased forced and voluntary exercise ability compared to control; they spent significantly less time running on the voluntary wheels than control mice for the first week post injection (Day 1: 0.2 + 0.1 hr vs. 2.2 + 0.6 hr, Day 3: 2.1 + 0.3 hr vs. 4.4 + 0.4,  p< 0.05, repeated measures ANOVA) and experienced more slips during forced exercise than control mice on day 3 (25.2 + 7.3 vs. 4.5 + 1.7, p< 0.05, repeated measures ANOVA).  The limping score was increased for MIA treated mice only for day 1; while the von Frey threshold showed high inter-animals variability and did not reveal any significant changes between the MIA and control group.  Conclusion: The use of voluntary exercise for the investigation of osteoarthritis offers several advantages over the limping score, von Frey withdrawal or forced exercise:  Knee joint function is directly assessed over a prolonged time while causing no distress to the animals. In addition, it is objective, generates little variation and can be applied at low cost. This new technique could enhance our understanding of arthritis and help in developing new therapies.