Transforming Growth Factor β1/Vascular Endothelial Growth Factor Signaling Pathway Regulates Chondrocytes Dedifferentiation

Abstract

This study investigated the interrelation between TGF-β and VEGF during CH dedifferentiation. A high dose of TGF-β1 was used to induce CHs dedifferentiation, and the effect of the TGF-β receptor inhibitor containing ALK1 and ALK5 on VEGF expression was explored. A VEGF inhibitor was used to investigate whether it prevented TGF-β1-induced CHs dedifferentiation. Low-dose TGF-β1 contributed to the steady-state of CHs, but a high dose significantly decreased collagen II and SOX-9 expression and increased collagen X, Runx2, and MMP-13 mRNA expression, accompanied by a marked upregulation of VEGF. ALK5 inhibition exacerbated the side effect caused by high-dose TGF-β1, while ALK1 inhibition had the opposite effect. Suppression of ALK1 and ALK5 contributed to the prevention of the VEGF level under high-dose TGF-β1 conditions. The suppression of VEGF protected the content of chondrogenic genes and suppressed the expression of dedifferentiated genes. In conclusion, high-dose TGF-β1 upregulated VEGF expression by ALK1 and ALK5 activation, resulting in CHs dedifferentiation. Suppression of ALK1 is an effective way to interrupt the TGF-β1/VEGF signaling pathway induced CH dedifferentiation.