The potential anti-oxidant and anti-inflammatory mechanisms of tempol on MIA-induced osteoarthritis in rats can be collectively demonstrated through its ability to provoke collateral suppression of the catabolic signaling cascades including TGF-β1/SMAD3/NOX4, and NOX4/ROS/p38MAPK/NF-κB, which in turn results in decreasing MMPs production, reducing catabolic inflammatory sequels, limiting structural alterations, and reducing pain. This evidence concerns the gene SMAD3 and osteoarthritis.