Moderate Exercise Inhibits the Development of Knee Osteoarthritis-like Changes in a Rat Model of Diet-induced Obesity

Purpose: Osteoarthritis (OA) is a debilitating chronic disease. Currently, there is no cure or disease modifying treatment for OA. Recently, OA linked to obesity-related metabolic factors has been distinguished as metabolic OA phenotype. Using a rat model, it has been shown that a high-fat high-sucrose diet leads to increased body fat, systemic inflammation, local inflammation in the knee, and metabolic knee OA in rats within 12-weeks. Exercise is known to be an effective modulator of body fat and systemic inflammation, but its effect on metabolic OA have not been studied systematically. The purpose of this study was to determine the effects of moderate exercise on the onset of knee OA in rats exposed to a high-fat high-sucrose diet. Methods: Twenty-four male, 12-week old Sprague Dawley rats, fed with a high-fat high-sucrose diet to induce obesity (40% fat and 45% sucrose, DYET# 102412, Dyets, United States) were randomized into a moderate exercise (DIO+E, n=12) or a sedentary control group (DIO, n=12). The moderate exercise intervention consisted of a progressive treadmill training program for 12 weeks, 30 minutes per day, 5 days a week; which corresponds to the recommended minimal physical activity guidelines in humans. Four days following the intervention protocol, rats were lightly anaesthetized, body composition was measured via Dual X-ray absorptiometry (DXA), rats were euthanized, and the left knee joints harvested. Histologic serial sections of the knee were cut at 10 μm thickness and stained with Safranin O, Hematoxylin, and Fast Green. Two independent graders assessed all sections in a blinded manner using the modified Mankin histology scoring system. Chi-square test was used to assess differences in knee joints between groups, while Mann-Whitney U-Tests were used to assess differences in knee joints between groups across four knee joint locations: medial tibial plateau (MTP), lateral tibial plateau (LTP), medial femoral condyle (MFC), and lateral femoral condyle (LFC). Independent-Samples t-Test was used to assess differences in body fat composition between groups (for all tests, α=0.05). Results: Moderate exercise was not effective in preventing the diet-dependent increases in body fat composition in this cohort to a statistically significant degree (p=0.146, Figure 1-A). Despite this, the observed reduction of 3.9% in body fat is thought to be clinically relevant, as even a reduction of 3.5% of body fat has been reported to improve knee function by 28%. The improvement in knee function may be mediated by a reduction in systemic and local inflammation associated with the reduced body fat. Modified Mankin scores were lower in DIO+E compared to DIO group knees (p=0.002). Specifically, the MTP and MFC compartments had significantly lower modified Mankin scores in DIO+E compared to DIO group rats (p=0.022 and p=0.012, respectively – Figure 1B). This finding suggests a protective effect of moderate exercise on the medial compartment in the rat knee, possibly via a direct influence on the loading of cartilage in the medial compartment, an indirect effect due to modulation of diet-induced intra-articular inflammation, or a combination of these two factors. Conclusions: Despite the lack of a statistically significant reduction in body fat in DIO+E group rats compared to DIO group rats, exercise reduced the development of OA-like changes in the medial compartment of rat knees exposed to a high-fat high-sucrose diet. These findings suggest that exercise/loading is a modifiable factor for the prevention of metabolic OA in the knee.