Abstract
The existence of a link between estrogen deprivation and osteoarthritis (OA) in postmenopausal women suggests that 17β-estradiol (17β-E2) may be a modulator of cartilage homeostasis. Here, we demonstrate that 17β-E2 stimulates, via its receptor human estrogen receptor α 66 (hERα66), 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 hERα66 was mediated by “GC” binding sites of the −266/−63-bp promoter, through physical interactions between ERα, Sp1/Sp3, Sox9, and p300, as demonstrated in chromatin immunoprecipitation (ChIP) and Re-Chromatin Immuno-Precipitation (Re-ChIP) assays in primary and dedifferentiated cells. 17β-E2 and hERα66 increased the DNA-binding activities of Sp1/Sp3 and Sox-9 to both COL2A1 promoter and enhancer regions. Besides, Sp1, Sp3, and Sox-9 small interfering RNAs (siRNAs) prevented hERα66-induced transactivation of COL2A1, suggesting that these factors and their respective cis-regions are required for hERα66-mediated COL2A1 up-regulation. Our results highlight the genomic pathway by which 17β-E2 and hERα66 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 17β-E2 could promote chondrocyte redifferentiation.
Key messages
• 17β-E2 up-regulates type II collagen gene expression in articular chondrocytes.
• An ERα66/Sp1/Sp3/Sox-9/p300 protein complex mediates this stimulatory effect.
• This heteromeric complex interacts and binds to Col2a1 promoter and enhancer in vivo.
• Our findings highlight a new regulatory mechanism for 17β-E2 action in chondrocytes.
• 17β-E2 might be an attractive candidate for cartilage engineering applications.
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Acknowledgments
This work was supported by the French Ministry of Research and Technology and is a part of a more global program on tissue engineering of articular cartilage of the laboratory supported by the French Agency of Research (ANR: Agence Nationale de la Recherche, Tecsan, PROMOCART) and the Regional Council of Lower-Normandy.
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The authors declare that they have no conflict of interest.
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Safa Moslemi and Philippe Galéra contributed equally to this work.
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Maneix, L., Servent, A., Porée, B. et al. Up-regulation of type II collagen gene by 17β-estradiol in articular chondrocytes involves Sp1/3, Sox-9, and estrogen receptor α. J Mol Med 92, 1179–1200 (2014). https://doi.org/10.1007/s00109-014-1195-5
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DOI: https://doi.org/10.1007/s00109-014-1195-5