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      Regulation of chondrocyte apoptosis in osteoarthritis by endoplasmic reticulum stress

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          Abstract

          Osteoarthritis (OA), a common degenerative joint disease, is characterized by the apoptosis of chondrocytes as a primary pathophysiological change, with endoplasmic reticulum stress (ERS) playing a crucial role. It has been demonstrated that an imbalance in endoplasmic reticulum (ER) homeostasis can lead to ERS, activating three cellular adaptive response pathways through the unfolded protein response to restore ER homeostasis. Mild ERS exerts a protective effect on cells, while prolonged ERS that disrupts the self-regulatory balance of the ER activates apoptotic signaling pathways, leading to chondrocyte apoptosis and hastening OA progression. Hence, controlling the ERS signaling pathway and its apoptotic factors has become a critical focus for preventing and treating OA. This review aims to elucidate the key mechanisms of ERS pathway-induced apoptosis, associated targets, and regulatory pathways, offering valuable insights to enhance the mechanistic understanding of OA. It also reviews the mechanisms studied for ERS-related drugs or compounds for the treatment of OA.

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          Most cited references135

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          Activation of apoptosis signalling pathways by reactive oxygen species.

          Reactive oxygen species (ROS) are short-lived and highly reactive molecules. The generation of ROS in cells exists in equilibrium with a variety of antioxidant defences. At low to modest doses, ROS are considered to be essential for regulation of normal physiological functions involved in development such as cell cycle progression and proliferation, differentiation, migration and cell death. ROS also play an important role in the immune system, maintenance of the redox balance and have been implicated in activation of various cellular signalling pathways. Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis. Apoptosis is a highly regulated process that is essential for the development and survival of multicellular organisms. These organisms often need to discard cells that are superfluous or potentially harmful, having accumulated mutations or become infected by pathogens. Apoptosis features a characteristic set of morphological and biochemical features whereby cells undergo a cascade of self-destruction. Thus, proper regulation of apoptosis is essential for maintaining normal cellular homeostasis. ROS play a central role in cell signalling as well as in regulation of the main pathways of apoptosis mediated by mitochondria, death receptors and the endoplasmic reticulum (ER). This review focuses on current understanding of the role of ROS in each of these three main pathways of apoptosis. The role of ROS in the complex interplay and crosstalk between these different signalling pathways remains to be further unravelled during the coming years.
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            Mechanisms, regulation and functions of the unfolded protein response

            Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the unfolded protein response (UPR), a signal transduction pathway that senses the fidelity of protein folding in the ER lumen. The UPR transmits information about protein folding status to the nucleus and cytosol to adjust the protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.
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              ER stress-induced cell death mechanisms.

              The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Section entitled: Cell Death Pathways. © 2013.
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                Author and article information

                Contributors
                Journal
                Cell Stress Chaperones
                Cell Stress Chaperones
                Cell Stress & Chaperones
                Elsevier
                1355-8145
                1466-1268
                06 November 2024
                December 2024
                06 November 2024
                : 29
                : 6
                : 750-763
                Affiliations
                [1 ]Taizhou Hospital of Traditional Chinese Medicine, Taizhou, Jiangsu Province, China
                [2 ]The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
                [3 ]Anhui Acupuncture Hospital, Hefei, Anhui Province, China
                Author notes
                [* ]Corresponding author. 923942026@ 123456qq.com
                Article
                S1355-8145(24)00126-3
                10.1016/j.cstres.2024.11.001
                11626768
                39515603
                bf7e78d6-ebda-474e-9c85-089de6bb28fc
                © 2024 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 5 August 2024
                : 1 November 2024
                : 4 November 2024
                Categories
                Review Paper

                Molecular biology
                osteoarthritis,endoplasmic reticulum stress,apoptosis,unfolded protein response,review

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