Up-regulation of type II collagen gene by 17β-estradiol in articular chondrocytes involves Sp1/3, Sox-9, and estrogen receptor α

Laure Maneix (1) , Aurélie Servent (1) , Benoît Porée (1) , David Ollitrault (1) , Thomas Branly (1) , Nicolas Bigot (1) , Noureddine Boujrad (2) , Gilles Flouriot (2) , Magali Demoor (1) , Karim Boumediene (1) , Safa Moslemi (1) , Philippe Galéra (1)

1 MILPAT - Microenvironnement cellulaire et pathologie
2 Interactions Cellulaires et Moléculaires

The existence of a link between estrogen deprivation and osteoarthritis (OA) in postmenopausal women suggests that 17-estradiol (17-E2) may be a modulator of cartilage homeostasis. Here, we demonstrate that 17-E2 stimulates, via its receptor hER66 (human estrogen receptor  66), type II collagen expression in differentiated and dedifferentiated (reflecting the OA phenotype) articular chondrocytes. Transactivation of type II collagen gene (COL2A1) by ligand independent transactivation domain (AF-1) of hER66 was mediated by ‘GC’ binding sites of the -266/-63 bp promoter, through physical interactions between ER, Sp1/Sp3, Sox9 and p300, as demonstrated in ChIP and Re-ChIP assays in primary and dedifferentiated cells. 17-E2 and hER66 increased the DNA-binding activities of Sp1/Sp3 and Sox-9 to both COL2A1 promoter and enhancer regions. Besides, Sp1, Sp3 and Sox-9 siRNAs prevented hER66-induced transactivation of COL2A1, suggesting that these factors and their respective cis-regions are required for hER66-mediated COL2A1 up-regulation. Our results highlight the genomic pathway by which 17-E2 and hER66 modulate Sp1/Sp3 heteromer binding activity and simultaneously participate in the recruitment of the essential factors Sox-9 and p300 involved respectively in the chondrocyte differentiated status and COL2A1 transcriptional activation. These novel findings could therefore be attractive for tissue engineering of cartilage in OA, by the fact that 17-E2 could promote chondrocyte redifferentiation.

Keywords: Type II collagen (COL2A1) gene; Estrogen receptor ; 17-estradiol; Sp1/Sp3; Sox proteins; Chondrocytes; Cartilage; Osteoarthritis

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology

Laure Maneix, Aurélie Servent, Benoît Porée, David Ollitrault, Thomas Branly, et al.. Up-regulation of type II collagen gene by 17β-estradiol in articular chondrocytes involves Sp1/3, Sox-9, and estrogen receptor α. Journal of Molecular and Genetic Medicine, 2014, 92 (11), pp.1179-1200. ⟨10.1007/s00109-014-1195-5⟩. ⟨hal-01082937⟩