Rapid increase in aging populations is an urgent problem because older adults are more likely to suffer from disabilities and age-related diseases (ARDs), burdening healthcare systems and society in general. ARDs are characterized by the progressive deterioration of tissues and organs over time, eventually leading to tissue and organ failure. To date, there are no effective interventions to prevent the progression of ARDs. Hence, there is an urgent need for new treatment strategies. Ferroptosis, an iron-dependent cell death, is linked to normal development and homeostasis. Accumulating evidence, however, has highlighted crucial roles for ferroptosis in ARDs, including neurodegenerative and cardiovascular diseases. In this review, we a) summarize initiation, regulatory mechanisms, and molecular signaling pathways involved in ferroptosis, b) discuss the direct and indirect involvement of the activation and/or inhibition of ferroptosis in the pathogenesis of some important diseases, and c) highlight therapeutic targets relevant for ARDs.

Collagens serve essential mechanical functions throughout the body, particularly in the connective tissues. In articular cartilage, collagens provide most of the biomechanical properties of the extracellular matrix essential for its function. Collagen plays a very important role in maintaining the mechanical properties of articular cartilage and the stability of the ECM. Noteworthily, many pathogenic factors in the course of osteoarthritis and rheumatoid arthritis, such as mechanical injury, inflammation, and senescence, are involved in the irreversible degradation of collagen, leading to the progressive destruction of cartilage. The degradation of collagen can generate new biochemical markers with the ability to monitor disease progression and facilitate drug development. In addition, collagen can also be used as a biomaterial with excellent properties such as low immunogenicity, biodegradability, biocompatibility, and hydrophilicity. This review not only provides a systematic description of collagen and analyzes the structural characteristics of articular cartilage and the mechanisms of cartilage damage in disease states but also provides a detailed characterization of the biomarkers of collagen production and the role of collagen in cartilage repair, providing ideas and techniques for clinical diagnosis and treatment.

A role for ferroptosis in articular cartilage destruction associated with rheumatoid arthritis (RA) has not been identified. We previously reported transient receptor potential melastatin 7 (TRPM7) expression was correlated with RA cartilage destruction. Herein, we further characterized a role for TRPM7 in chondrocyte ferroptosis. The expression of TRPM7 was found to be elevated in articular chondrocytes derived from adjuvant arthritis (AA) rats, human RA patients, and cultured chondrocytes treated with the ferroptosis inducer, erastin. TRPM7 knockdown or pharmacological inhibition protected primary rat articular chondrocytes and human chondrocytes (C28/I2 cells) from ferroptosis. Moreover, TRPM7 channel activity was demonstrated to contribute to chondrocyte ferroptosis by elevation of intracellular Ca²⁺. Mechanistically, the PKCα-NOX4 axis was found to respond to stimulation with erastin, which resulted in TRPM7-mediated chondrocyte ferroptosis. Meanwhile, PKCα was shown to directly bind to NOX4, which could be reduced by TRPM7 channel inhibition. Adeno-associated virus 9-mediated TRPM7 silencing or TRPM7 blockade with 2-APB alleviated articular cartilage destruction in AA rats and inhibited chondrocyte ferroptosis. Collectively, both genetic and pharmacological inhibitions of TRPM7 attenuated articular cartilage damage and chondrocyte ferroptosis via the PKCα-NOX4 axis, suggesting that TRPM7-mediated chondrocyte ferroptosis is a promising target for the prevention and treatment of RA.

Background: Acid-sensing ion channel 1a (ASIC1a), the primary acid sensors in the nervous system, has been studied earlier in various physiopathologic conditions. However, little is known about the role of ASIC1a in endplate chondrocytes in intervertebral discs (IVDs). Methods: The expression of ASICs was examined in rat endplate chondrocytes. Effects of treatment with ASIC1a small interfering RNA (siRNA) or selective blocker (PcTX1) on acid-induced intracellular Ca²⁺ concentration ([Ca²⁺]i) and cell apoptosis were investigated. ASIC1a involved in Ca²⁺-mediated apoptotic signals in acid-induced endplate chondrocyte apoptosis was also assessed. Results: We showed that ASIC1a is expressed in rat endplate chondrocytes, and blockade of ASIC1a using ASIC1a-siRNA or PcTX1 inhibited acid-induced cell apoptosis and elevation of [Ca²⁺]i. We also demonstrated that the acid-induced [Ca²⁺]i increase via ASIC1a is involved in endplate chondrocyte apoptosis. Moreover, blocking of ASIC1a-mediated [Ca²⁺]i elevation inhibited activation of acid-induced calcium-dependent proteases and decreased BAD phosphorylation in endplate chondrocytes. Similarly, extracellular acidosis induced cytochrome C translocation from the mitochondria to the cytoplasm and activation of caspase-9 and caspase-3, which was inhibited by ASIC1a-siRNA or PcTX1. Conclusion: ASIC1a activation in endplate chondrocytes may trigger Ca²⁺-dependent proteases activity and signaling, which leads to apoptosis of endplate chondrocytes in IVDs.