Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review).

Degenerative joint diseases, such as osteoarthritis (OA), intervertebral disc degeneration (IVDD) and rheumatoid arthritis (RA), cause pain and disability worldwide. Globally, OA affects >500 million individuals, IVDD affects 40-60% of adults and RA affects 0.5-1% of the global population. Current treatments (such as non-steroidal anti-inflammatory drugs and corticosteroids for OA, conservative management and spinal surgery for IVDD, and disease-modifying anti-rheumatic drugs/biologics for RA) focus on symptom relief and inflammation control, but they do not prevent disease progression nor restore damaged tissue. Furthermore, these treatments are often associated with risks of systemic side effects (such as gastrointestinal bleeding, cardiovascular events and immunosuppression) or surgical complications (such as infection and implant failure). Although accumulating evidence implicates mitochondrial dysfunction and excessive reactive oxygen species (ROS) in the pathogenesis of these disorders, strategies that directly target mitochondrial oxidative stress are yet to be developed and translated into the clinic. In the present study this gap in the knowledge was addressed by systematically reviewing mitochondria-targeted antioxidant therapies and mitochondrial quality-control mechanisms due to their potential as novel, disease-modifying approaches for degenerative joint diseases. The preclinical efficacy of mitochondria-directed antioxidants (such as mitoquinone, MitoTEMPO, 10-(6'-plastoquinonyl) decyltriphenylphosphonium and Szeto-Schiller-31) in alleviating ROS-induced cellular damage, inhibiting apoptosis/pyroptosis and preserving extracellular matrix integrity in OA, IVDD and RA models were summarized. Additionally, strategies to enhance mitophagy (such as through PTEN-induced kinase 1/Parkin), rebalance mitochondrial dynamics (such as through the dynamin-related protein 1/mitofusin 1/2) and activate antioxidant signaling pathways (such as nuclear factor erythroid 2-related factor 2 and sirtuin 3) were highlighted. The present study identified key translational challenges (such as optimal delivery systems, long-term safety and clinical validation) and suggested integrated therapeutic frameworks that combine targeted antioxidants with advanced drug carriers and adjunctive treatments. Mitochondria-focused interventions may have potential as the next generation of disease-modifying treatments for OA, IVDD and RA.