Hypoxia inducible factor 1 alpha down‐regulates type i collagen through Sp3 transcription factor in human chondrocytes

Cartilage engineering is one challenging issue in regenerative medicine. Low oxygen tension or hypoxia inducible factor‐1 (HIF‐1α) gene therapy are promising strategies in the field of cartilage repair. Previously, we showed that hypoxia and its mediator HIF‐1 regulate matrix genes expression (collagens and aggrecan). Here, we investigated the molecular mechanism involved in the regulation of type I collagen (COL1A1) by HIF‐1 in human articular chondrocytes. We show that HIF‐1α reduces COL1A1 transcription, through a distal promoter (−2300 to −1816 bp upstream transcription initiation site), containing two GC boxes that bind Sp transcription factors (Sp1/Sp3). Sp1 acts as a positive regulator but is not induced by HIF‐1. COL1A1 inhibition caused by HIF‐1 implies only Sp3, which accumulates and competes Sp1 binding on COL1A1 promoter. Additionally, Sp3 ectopic expression inhibits COL1A1, while Sp3 knockdown counteracts the downregulation of COL1A1 induced by HIF‐1. In conclusion, we established a new regulatory model of COL1A1 regulation by HIF‐1, and bring out its relationship with Sp3 transcription factor. In a fundamental level, these findings give insights in the mechanisms controlling COL1A1 gene expression. This may be helpful to improve strategies to impair type I collagen expression during chondrocyte differentiation for cartilage engineering. © 2016 IUBMB Life, 68(9):756–763, 2016