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. 2018 Aug 3;19(8):2282. doi: 10.3390/ijms19082282

Figure 2.

Figure 2

FGF2, TGF-β and inflammatory cytokine induced catabolic and pro-inflammatory signaling in human OA AC. The major components of inflammatory cytokine, FGF2 and TGF-β activated nuclear factor kappa B (NF-κB), mitogen activated protein kinase (MAPK), and SMA- and MAD-related protein (SMAD) signaling as well as their transcriptional targets in human OA AC are depicted. Micro RNAs (miRNAs) upregulated in human OA AC are indicated in red, miRNAs downregulated in human OA AC are indicated in green. For miRNAs with contradictory regulation a black font is chosen. The small arrows beside the miRNAs pointing downwards indicate direct or indirect inhibition of the signaling component by the miRNA, whereas small upward arrows indicate direct or indirect activation of the signaling component by the miRNA. As illustrated, there is an intense crosstalk between the individual pathways. In human OA AC, expression of pro-catabolic target genes is mediated by NF-κB, MAPK and SMAD signaling, whereas pro-inflammatory targets are activated downstream of MAPK and NF-κB signaling. Advanced stages of OA are characterized by activation of inflammatory cytokine signaling. On miRNA level there is primarily a net upregulation of IL-6, whereas both positive and negative regulation of NF-κB signaling is reported. Moreover, in human OA AC upregulation of CCN2 and significantly enhanced activation of extracellular signal-regulated kinase (ERK), JUN N-terminal kinase (JNK) and p38 MAPK pathways has been documented. Yet, evidence for ERK signaling regulation by miRNA is contradictory, whereas JNK and p38 activation is a common downstream event after inflammatory cytokine, FGF2 and TGFβ pathway activation with no direct miRNA regulation reported in OA AC to date. TGF-β signaling is globally downregulated in OA AC with especially negative regulation of the anabolic SMAD3 mediated pathway which is both evident on protein and miRNA level. In addition, in particular at miRNA level, reversal of negative regulation of MMP-13 is obvious in OA AC.