Tyr-Tyr-Glu Tripeptide for Regeneration of Articular Cartilage through Chondrogenic Differentiation of Mesenchymal Stem Cells

Cell-based therapy accompanying articular cartilage regeneration is very promising as one of osteoarthritis (OA) treatments. Here, we report that Tyr-Tyr-Glu (YYE) is effective for articular cartilage regeneration through chondrogenic differentation of mesenchymal stem cells (MSCs). The expression of COL II, COMP, ACAN, and COL X at the mRNA and/or protein levels, together with Alcian Blue and Safranin O staining of 3-dimensionally cultured cell pellets, consistently demonstrated that YYE is an effective chondrogenic promoter of MSCs. Western blot, immunofluorescence, and molecular docking studies suggested that the chondrogenic up-regulation by YYE is mediated through YYE binding to FC-1, which induces translocation of core-binding factor β subunit (CBFβ) from the cytosol into the nucleus, followed by up-regulation of runt-related transcription factor 1 (RUNX1), which is a key factor for chondrogenic differentiation of MSCs. In particular, intra-articular injection of YYE to mouse OA models led to a significant improvements of OA as indicated by lowering OARSI grades and subchondral bone plate thickness, and thus proved its articular cartilage regeneration efficacy.