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. 2020 Sep 14;9(9):290. doi: 10.3390/biology9090290

Figure 2.

Figure 2

Transcription factors involved in extracellular matrix (ECM) metabolism. Model of how transcription factors are involved in the regulation of ECM production and degradation. Healthy chondrocytes synthesize ECM proteins such as ACAN and COL2A1. Important transcription factors for these genes are SOX5, SOX6, SOX9, and NFAT. In addition, in a healthy chondrocyte, matrix-degrading enzymes, such as MMPs and ADAMTSs, are expressed at a low level or not at all. These genes are silenced by epigenetic modifications. During osteoarthritis (OA), epigenetic changes occur by chromatin remodelers, resulting in either a conformation to euchromatin or heterochromatin, depending on the gene. In early OA, chondrocytes increase the production of important ECM proteins. One of the proposed mechanisms for this increase is the enhanced activation of transcription factors such as SOX9. SIRT1 can acetylate SOX9, which results in the recruitment of HAT cofactors such as p300 and GCN5, which, in turn, hyperacetylate surrounding histones. At this stage, transcription factors are recruited to the promoter regions of the ECM-degrading enzyme genes, such as AP-1, RUNX2, NFAT, and NFκB, and transcription takes place. In late OA chondrocytes, transcription levels of ECM-degrading enzymes increase, together with a loss of ECM production, as there are altered expression and function of transcription factors that are important for both these processes. Furthermore, epigenetic changes also occur, and, together, this results in the silencing of the ECM genes. MMP = matrix metalloproteinase; ADAMTS = a disintegrin and metalloproteinase with thrombospondin motif; AP-1 = activator protein 1; RUNX2 = runt-related transcription factor 2; NFAT = nuclear factor of activated T-cells; HAT = histone acetyltransferase; NFκB = nuclear factor kappa B; ACAN = aggrecan; COL2A1 = collagen type II; SOX5 = SRY-BOX transcription factor 5; SOX6 = SRY-BOX transcription factor 6; SOX9 = SRY-BOX transcription factor 9; HIF2α = hypoxia-inducible factor 2-alpha; TCF/LEF = T-cell factor/lymphoid enhancer factor.