Assessment of the effects of exercise on a murine model of OA

Purpose
International guidelines recommend exercise to delay rapid progression of osteoarthritis (OA). Numerous studies have shown that land-based exercise regimes, when performed regularly, leads to an improvement in joint mobility and pain. In vivo models of OA mimic many of the parameters of post-traumatic human OA. Destabilization of the medial meniscus (DMM) in rodents results in progressive development of OA with cartilage damage, osteosclerosis, mild synovitis, ligament damage/calcification and osteophyte formation. However, the limited data published on the effects of exercise on joint pathology is ambiguous especially with regard to the specific benefit to joint tissues. Notably, some rodent studies suggest a worsening of pathology after exercise. This study aims to examine in detail the effect of mild forced treadmill exercise on the joint pathology by utilizing the murine DMM model of OA.

Method
DMM or sham surgery was performed on 10-week-old adult male (25–30g) C57BL/6 (Envigo, UK). Exercise was conducted in a regulated rotating wheel, forcing the mice to walk 800 m/day at a speed of 3.8 m/min, with an 18-second break every 4 minutes (Campden Instruments Ltd., Loughborough). Exercise started 1 week after DMM surgery and continued 5 days/week for 3 or 7 weeks. Knee joints were subsequently harvested for assessment by microcomputed tomography (4.5 μm resolution) and histology (5 μm sections). Subcutaneous, gonadal and brown fat pads were dissected and weighted (wet weight), as well as the quadriceps and soleus muscles. Overnight activity was measured with an activity meter (Bioseb, France). All procedures were in accordance with Home Office regulations. Data was analyzed by repeated measures 2-way ANOVA or standard 2-way ANOVA.

Results
Mice in the forced exercised group showed significantly less weight gain (P=0.0057), regardless of the type of surgery (P=0.939), reflecting the significant loss of subcutaneous (P=0.0027) and gonadal (P=0.0032) fat pad weight in the exercise group. There were no changes in muscle mass, confirming that the exercise regime was mild. Oovernight activity was not affected by daily forced exercise. At 4 weeks post-surgery, subchondral bone sclerosis on the medial tibial condyle was significantly decreased in the exercised DMM group when compared to the non-exercised DMM group (ipsi-contra % BV/TV Control=9.1±1.22, Exercise=4.3±1.07, P=0.01). This protection was lost by week eight. Tibial trabecular bone of the operated leg was found to be significantly different only in the exercise DMM group, when compared to the contralateral leg, 4 and 8 weeks after DMM. Trabecular bone was more connected (Tb.Pf.: contra=0.02±3x10-5, ipsi=0.19±3x10-5), more plate-like (SMI: Contra=1.89±0.06, ipsi=1.79±0.10) and less organized (DA: Contra=2.17±0.06, ipsi=2.3±0.07). Importantly, histological cartilage damage and synovitis scores showed no changes between the exercise and control groups in either 4 or 8 weeks post-DMM.

Conclusions
Whilst exercise in recommended to OA patients, there is a need for better understanding of how this impacts joint tissues. In this study, we aimed to determine in murine OA whether exercise is beneficial or detrimental to disease progression. Our key finding is that the mild form of forced exercise utilized in these studies does not accelerate and/or exacerbate joint OA pathology, and indeed there may be transient improvement in subchondral osteosclerosis early in the exercise regime.