ABSTRACT
             Background and objectives: Matrix metalloproteinase-13 (MMP-13) and activin receptor-like kinase 5 (ALK5) are considered as important factors contributing to knee osteoarthritis (OA) pathogenesis. Here, we compared therapeutic effects of mesenchymal stem cells (MSCs), ozone and exercise training alone and combined on expression of MMP-13 and ALK5 in rats with knee OA.
            Methods: Knee OA was induced by a surgical method. Rats with OA were then randomly divided into several groups, including model, MSCs, ozone, exercise, MSCs + ozone, MSCs + exercise, ozone + exercise and MSCs + ozone + exercise groups. Expression of MMP-13 and ALK5 genes was evaluated using RT-PCR. Data were analyzed using SPSS software at significance of 0.05. 
            Results: Expression of MMP-13 and ALK5 differed significantly between the study groups (P<0.0001). Knee OA was significantly associated with overexpression of MMP-13 and ALK5 in the cartilage tissue of rats with knee OA. Combined therapy with MSCs, ozone and exercise significantly decreased the expression of MMP-13 and ALK5 in the cartilage of rats with OA (P<0.001). Although MSCs, ozone and exercise training were effective to mitigate expression of MMP-13 and ALK5 genes, ozone therapy was more effective compared to the other two therapies.
            Conclusion: Although ozone, MSCs and exercise training alone could decrease the expression of MMP-13 and ALK5 genes, combined therapy with MSC, ozone and exercise is more effective.  
            Keywords: Osteoarthritis, O3, MSCs, exercise, MMP-13, ALK5.