Osteoarthritis (OA) is the most common chronic disease. According to the World Health Organization, an estimated 9.6 percent of men and 18.0 percent of women over the age of 60 suffer from symptoms of OA. Despite this high prevalence of osteoarthritis, no drugs are currently available that slow the progression of the disease. Oxidative stress processes have been described as an important factor in various diseases and have recently been mentioned in the development of osteoarthritis. Evidence for the use of antioxidants to reduce the severity of osteoarthritis is slowly accumulating, and the mechanisms of cartilage protection in joint tissue are still in need of further study to demonstrate potential benefit to patients. A new study implies that the transcriptional repressor Bach-1 and its downstream target HO-1 are important players in this process. Osteoarthritis is a complex multifactorial degenerative disease with risk factors including aging, mechanical disturbances, genetics and obesity. Despite its high prevalence, no treatment is currently available to prevent or delay disease progression. The features of osteoarthritis involve degradation of the extracellular matrix of articular cartilage, subchondral osteosclerosis, synovial activation and thickening, and bone flab formation. Various pathways have also been associated with osteoarthritis, particularly those involving phenotypic changes in articular chondrocytes. In recent studies, a novel association between osteoarthritis and oxidative stress regulation has been proposed as a new potential therapeutic target. Oxidative stress is thought to damage many cells, occurring mainly during disease and aging. Therefore, there are many research groups conducting studies on the pathogenesis of OA and the effects of antioxidants. In the study by Takada et al. 2 different mouse models of osteoarthritis were compared, a mechanically unstable murine model caused by aging knee surgery and a homologous mouse with Bach-1 deletion.Bach-1 decreases transcription of HO-1, which regulates antioxidants.Bach-1 deletion promotes HO-1 expression in mice, thereby protecting the joints from developing osteoarthritis after aging and trauma. Bach-1 deletion in vitro also resulted in a decrease in MMP-13 and ADAMTS-5 gene expression in response to cytokine treatment, along with altered protection against cartilage loss. The protective effects are thought to be important for cellular homeostasis through increased self-phagocytosis, as well as reduced apoptosis. Some of the protective effects of Bach-1 deletion were lost after treatment with small molecule interferons targeting HO-1. From these data the authors conclude that maintaining HO-1 levels by inhibiting Bach-1 can be used to protect against the progression of osteoarthritis caused by aging and post-trauma. Another antioxidant regulator is the transcription factor nuclear factor Nrf2. Nrf2 deficiency leads to exacerbation of osteoarthritis in mice modeled for post-traumatic osteoarthritis and in mice modeled for sodium iodine-induced inflammation. The induction of Nrf2 activation and HO-1 expression with a histone deacetylase inhibitor (troguloside A) inhibited chondrocyte interleukin (IL)-1β-induced MMP gene expression. Similarly, in vivo studies have found a reduction in osteoarthritis and a decrease in MMP expression, as well as an increase in HO-1, following the use of troglitazone A. These effects were dependent on the presence of Nrf2. Turnip sulfur is a natural and potent activator of Nrf2. Turnip sulfur has been shown to similarly induce gene expression of HO-1, a downstream target of Nrf2. In this study, Davidson et al. also demonstrated that radothionein treatment reduced IL-1β-induced MMP gene expression. Turnip sulfur was able to reduce cytokine-induced cartilage degeneration in vitro and in vivo in a DMM model of cartilage degeneration. These studies, like Takad’s article, provide strong evidence that HO-1 may be an important protective factor against inflammation and in attenuating post-traumatic osteoarthritis. However, the role of HO-1 itself still needs further validation. Takada also found that Bach-1 deficiency increased autophagy, which may be associated with a protective protective effect against osteoarthritis in mice. Indeed, autophagy is a protective mechanism for cell survival in response to stress. In post-traumatic arthritis the use of the mTOR (mechanical target of rapamycin) inhibitor rapamycin activates autophagy, leading to a reduction in osteoarthritis. This was accompanied by a decrease in the osteoarthritis markers MMP-13 and collagen X and an increase in the autophagic marker LC3. Similarly, mTOR deficiency in chondrocytes protected osteoarthritis from progression and significantly reduced cartilage degeneration, apoptosis and synovial fibrosis. It appears from these studies that the mechanisms of HO-1 protection against osteoarthritis are complex and involve various pathways, including Nrf-regulated antioxidant response elements and autophagy. A deeper understanding of these pathways may uncover new therapeutic targets to slow the progression of osteoarthritis.