title: Hypoxia inducible factor 1 alpha down-regulates type i collagen through Sp3 transcription factor in human chondrocytes.
abstract: 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.
authors: EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.|Normandie University, UFR de médecine, Caen, France.
authors: Elise
authors: E
authors: Duval
authors: EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.|Normandie University, UFR de médecine, Caen, France.
authors: Mouloud
authors: M
authors: Bouyoucef
authors: EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.|Normandie University, UFR de médecine, Caen, France.|Département De Chirurgie Orthopédique, Clinique Saint-Martin, Caen, 14000, France.
authors: Sylvain
authors: S
authors: Leclercq
authors: EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.|Normandie University, UFR de médecine, Caen, France.|Fédération Hospitalo Universitaire SURFACE, Amiens, Rouen, Caen, France.
authors: Catherine
authors: C
authors: Baugé
authors: EA4652, Equipe BioConnecT, UNICAEN, Caen, CS, 14032, France.|Normandie University, UFR de médecine, Caen, France.|Fédération Hospitalo Universitaire SURFACE, Amiens, Rouen, Caen, France.
authors: Karim
authors: K
authors: Boumédiene
mesh_terms: D002357:Cartilage Diseases / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D018507:Gene Expression Regulation, Developmental; D015316:Genetic Therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051705:Sp3 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051705:Sp3 Transcription Factor
keywords: Sp transcription factors; cartilage; chondrocytes; collagen type I; gene expression; hypoxia; hypoxia-inducible factor 1