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      Progranulin regulation of autophagy contributes to its chondroprotective effect in osteoarthritis


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          Progranulin (PGRN) is a multifunctional growth factor involved in many physiological processes and disease states. The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progression of osteoarthritis (OA) led us to investigate the role of PGRN in the regulation of chondrocyte autophagy. PGRN knockout chondrocytes exhibited a deficient autophagic response with limited induction following rapamycin, serum starvation, and IL-1β-induced autophagy. PGRN-mediated anabolism and suppression of IL-1β-induced catabolism were largely abrogated in the presence of the BafA1 autophagy inhibitor. Mechanistically, during the process of OA, PGRN and the ATG5–ATG12 conjugate form a protein complex; PGRN regulates autophagy in chondrocytes and OA through, at least partially, the interactions between PGRN and the ATG5–ATG12 conjugate. Furthermore, the ATG5–ATG12 conjugate is critical for cell proliferation and apoptosis. Knockdown or knockout of ATG5 reduces the expression of ATG5–ATG12 conjugate and inhibits the chondroprotective effect of PGRN on anabolism and catabolism. Overexpression of PGRN partially reversed this effect. In brief, the PGRN-mediated regulation of chondrocyte autophagy plays a key role in the chondroprotective role of PGRN in OA. Such studies provide new insights into the pathogenesis of OA and PGRN-associated autophagy in chondrocyte homeostasis.

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          Osteoarthritis is a leading cause of disability and source of societal cost in older adults. With an ageing and increasingly obese population, this syndrome is becoming even more prevalent than in previous decades. In recent years, we have gained important insights into the cause and pathogenesis of pain in osteoarthritis. The diagnosis of osteoarthritis is clinically based despite the widespread overuse of imaging methods. Management should be tailored to the presenting individual and focus on core treatments, including self-management and education, exercise, and weight loss as relevant. Surgery should be reserved for those that have not responded appropriately to less invasive methods. Prevention and disease modification are areas being targeted by various research endeavours, which have indicated great potential thus far. This narrative Seminar provides an update on the pathogenesis, diagnosis, management, and future research on osteoarthritis for a clinical audience.
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            An overview of autophagy: morphology, mechanism, and regulation.

            Autophagy is a highly conserved eukaryotic cellular recycling process. Through the degradation of cytoplasmic organelles, proteins, and macromolecules, and the recycling of the breakdown products, autophagy plays important roles in cell survival and maintenance. Accordingly, dysfunction of this process contributes to the pathologies of many human diseases. Extensive research is currently being done to better understand the process of autophagy. In this review, we describe current knowledge of the morphology, molecular mechanism, and regulation of mammalian autophagy. At the mechanistic and regulatory levels, there are still many unanswered questions and points of confusion that have yet to be resolved. Through further research, a more complete and accurate picture of the molecular mechanism and regulation of autophagy will not only strengthen our understanding of this significant cellular process, but will aid in the development of new treatments for human diseases in which autophagy is not functioning properly.
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              The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse.

              To describe a histologic scoring system for murine osteoarthritis (OA) that can be applied universally to instability, enzymatic, transgenic and spontaneous OA models. Scientists with expertise in assessing murine OA histopathology reviewed the merits and drawbacks of methods described in the literature. A semi-quantitative scoring system that could reasonably be employed in any basic cartilage histology laboratory was proposed. This scoring system was applied to a set of 10 images of the medial tibial plateau and femoral condyle to yield 20 scores. These images were scored twice by four experienced scorers (CL, SG, MC, TA), with a minimum time interval of 1 week between scores to obtain intra-observer variability. An additional three novice scorers (CR, CL and MM) with no previous experience evaluated the images to determine the ease of use and reproducibility across laboratories. The semi-quantitative scoring system was relatively easy to apply for both experienced and novice scorers and the results had low inter- and intra-scorer variability. The variation in scores across both the experienced and novice scorers was low for both tibia and femur, with the tibia always having greater consistency. The semi-quantitative scoring system recommended here is simple to apply and required no specialized equipment. Scoring of the tibial plateaus was highly reproducible and more consistent than that of the femur due to the much thinner femoral cartilage. This scoring system may be a useful tool for both new and experienced scorers to sensitively evaluate models and OA mechanisms, and also provide a common paradigm for comparative evaluation across the many groups performing these analyses. Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                13 June 2022
                July 2023
                13 June 2022
                : 10
                : 4
                : 1582-1595
                [a ]Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China
                [b ]Department of Orthopaedics, The 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
                [c ]Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
                [d ]Department of Orthopaedics, The 2nd Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
                [e ]Chongqing Medical University Laboratory Animal Center, Chongqing Medical University, Chongqing 400016, China
                Author notes

                These authors contributed equally to this work.

                © 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

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

                : 27 January 2022
                : 3 May 2022
                : 21 May 2022
                Full Length Article

                anabolism, atg12, atg5, autophagy, catabolism, osteoarthritis, pgrn


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