Dysregulation of mechanisms is linked to the progression of osteoarthritis.
Osteoarthritis is characterized by inflammation and damage to cartilage and surrounding tissues.
, an iron-dependent cell death, is associated with oxidative stress and chondrocyte dysfunction in osteoarthritis.
, which promotes inflammation through cytokine release, exacerbates joint inflammation and disease progression.
plays a dual role, offering protection in early stages but contributing to cartilage degeneration when dysregulated.
, a newly identified copper-dependent cell death, is linked to the dysfunction of bone and cartilage cells.
Apoptosis is accelerated by inflammatory factors and oxidative stress, further promoting chondrocyte death and disease progression.
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Osteoarthritis (OA) is a common and debilitating chronic disease characterized by severe inflammation and progressive damage to adjacent tissues and cartilage. Traditional risk factors such as obesity, gender, and aging have long been recognized as contributing factors to osteoarthritis. Emerging evidence highlights that the dysregulation of (PCD) plays a crucial role in the pathogenesis and progression of this disease. Numerous studies have shown that various forms of programmed cell death, including , , , , and apoptosis, are closely associated with osteoarthritis. Ferroptosis is an iron-dependent cell death driven by lipid peroxidation, which is related to iron overload and oxidative stress in osteoarthritis, leading to chondrocyte dysfunction and cartilage degradation. Pyroptosis, an inflammatory cell death, is triggered by the activation of inflammasomes, promoting the release of pro-inflammatory cytokines, exacerbating joint inflammation, and accelerating disease progression. Autophagy, a cellular self-degradation process, has a dual role in osteoarthritis: it acts as a protective mechanism against stress in the early stage, but when autophagy is dysregulated, it promotes cartilage degeneration. Cuproptosis is a newly discovered copper-dependent cell death pathway, and since copper metabolism dysregulation affects the function of bone and cartilage cells, it is associated with osteoarthritis. Apoptosis is an actively regulated cell death process controlled by genes and is mediated by two main pathways. The extrinsic pathway is activated when death ligands bind to receptors, triggering the activation of caspase-8 and caspase-3; the intrinsic pathway is initiated by cellular stress factors such as DNA damage, leading to mitochondrial damage and the activation of caspase-9 and caspase-3. In osteoarthritis, inflammatory factors and oxidative stress activate these two pathways, accelerating the apoptosis of chondrocytes and disease progression.This review systematically elaborates on these different types of programmed cell death and their specific roles in the development and progression of osteoarthritis. It also delves into the latest research on the molecular mechanisms of these programmed cell death pathways in the context of osteoarthritis, clarifying how they interact with other cellular processes to drive disease development. In addition, the review summarizes the clinical applications of therapeutic methods targeting programmed cell death in osteoarthritis. Ingredients from traditional Chinese medicine and other drugs show potential in regulating ferroptosis, pyroptosis, autophagy, cuproptosis, and apoptosis to alleviate the symptoms of osteoarthritis. For example,andcan prevent ferroptosis, whileand metformin can reduce pyroptosis. Regarding cuproptosis, copper chelators and copper ion carriers are also under investigation. Therapeutic strategies targeting mitochondrial autophagy and copper balance also offer hope for the treatment of osteoarthritis. Currently, non-coding RNAs, phytochemicals, and some proteins have been explored for their ability to inhibit the apoptosis of chondrocytes. In conclusion, a deep understanding of the mechanisms of programmed cell death in osteoarthritis not only provides new perspectives on the pathogenesis of the disease but also points the way for the development of targeted treatment strategies and the improvement of the treatment outcomes for osteoarthritis. Icariin Myristicin Matrine
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