Hypothesis on the regulation of miR-140 in human normal and osteoarthritic chondrocytes by TGF-β, SMAD3, NFAT3 and NFAT5. In normal human chondrocytes, mechano-transduction triggers calcium signaling and the subsequent translocation of NFAT3 to the nucleus, where it will up-regulate miR-140. NFAT5, activated under hypertonic stress, up-regulates WWP2 and miR-140 expression. As the levels of TGF-β are low in normal cartilage, the end result will be a positive regulation. In osteoarthritic cartilage, there is a marked increased expression of TGF-β and data showed that the expression levels of NFAT5 are decreased compared to normal human cartilage but those of NFAT3 are stable (data not shown). Thus, TGF-β will increase SMAD3 phosphorylation and directly inhibit miR-140. TGF-β will also indirectly down-regulate miR-140 by interfering with the translocation of NFAT3. Therefore, in osteoarthritic chondrocytes, the NFAT5 contribution will be lower and the TGF-β/SMAD3 negative regulation of miR-140 levels would prevail over the NFAT3 and NFAT5 positive regulation and account for the decrease in this miRNA in these cells. miRNA, microRNA; TGF-β, transforming growth factor β.