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

## TL;DR

A tripeptide called Tyr-Tyr-Glu promotes cartilage regeneration by encouraging stem cells to become cartilage cells, offering a new treatment for osteoarthritis.

## Contribution

YYE promotes chondrogenic differentiation of MSCs via binding to FC-1 and upregulating RUNX1, leading to cartilage regeneration in OA models.

## Key findings

- YYE enhances chondrogenic differentiation of MSCs as shown by COL II, COMP, and ACAN expression.
- YYE binding to FC-1 leads to CBFβ translocation and RUNX1 upregulation, promoting cartilage formation.
- Intra-articular injection of YYE in OA models improved cartilage regeneration and reduced OA severity.

## Abstract

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.