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      Transcription Factors in Cartilage Homeostasis and Osteoarthritis

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          Abstract

          Osteoarthritis (OA) is the most common degenerative joint disease, and it is characterized by articular cartilage loss. In part, OA is caused by aberrant anabolic and catabolic activities of the chondrocyte, the only cell type present in cartilage. These chondrocyte activities depend on the intra- and extracellular signals that the cell receives and integrates into gene expression. The key proteins for this integration are transcription factors. A large number of transcription factors exist, and a better understanding of the transcription factors activated by the various signaling pathways active during OA can help us to better understand the complex etiology of OA. In addition, establishing such a profile can help to stratify patients in different subtypes, which can be a very useful approach towards personalized therapy. In this review, we discuss crucial transcription factors for extracellular matrix metabolism, chondrocyte hypertrophy, chondrocyte senescence, and autophagy in chondrocytes. In addition, we discuss how insight into these factors can be used for treatment purposes.

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          Most cited references203

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          Mechanism and medical implications of mammalian autophagy

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            Transcription factors: from enhancer binding to developmental control.

            Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development.
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              TFEB links autophagy to lysosomal biogenesis.

              Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.
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                Author and article information

                Journal
                Biology (Basel)
                Biology (Basel)
                biology
                Biology
                MDPI
                2079-7737
                14 September 2020
                September 2020
                : 9
                : 9
                : 290
                Affiliations
                Experimental Rheumatology, Radboud University Medical Centre, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands; margot.neefjes@ 123456radboudumc.nl (M.N.); arjan.vancaam@ 123456radboudumc.nl (A.P.M.v.C.)
                Author notes
                [* ]Correspondence: peter.vanderkraan@ 123456radboudumc.nl ; Tel.: +31-24-16568
                Author information
                https://orcid.org/0000-0001-5473-4884
                Article
                biology-09-00290
                10.3390/biology9090290
                7563835
                32937960
                e3dcabca-7fa4-450d-a5a3-4a70dda614e2
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 July 2020
                : 07 September 2020
                Categories
                Review

                osteoarthritis,cartilage,transcription factors,gene expression analysis,transcriptome,transcriptional regulation

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