FIGURE 3.

The GDF‐5 signalling pathway and regulation of GDF‐5 expression. GDF‐5, binding to its receptors, activates Smad1/5/8 and subsequently form a complex with Smad 4. The complex then translocates into the nucleus, regulating the expression of target genes, such as COL2A1 and ACAN. In addition, GDF‐5 can induce phosphorylation of p38, which promotes nuclear translocation of Trps1, increasing COL2A1 gene expression in the chondrogenic cell line (ATDC5). During OA, the activated canonical Wnt signalling pathway induces the expression of the ECM‐degrading enzymes MMP13 in human chondrocytes, whereas GDF‐5 enhances DKK1 to inhibit this signalling. In addition, transcription factors YAP, SOX11, ZEB1 and PITX1 and microRNAs, miR‐449a and miR‐21, regulate GDF‐5 expression. Extracellular osmolarity, ranging from 380 to 450 mOsm, improves cellular responsiveness to GDF‐5