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

Abstract

The existence of a link between estrogen deprivation and osteoarthritis (OA) in postmenopausal women suggests that 17-estradiol (17-E 2 ) may be a modulator of cartilage homeostasis. Here, we demonstrate that 17-E 2 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-E 2 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-E 2 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-E 2 could promote chondrocyte redifferentiation. Keywords Key Messages 17-E 2 up-regulates type II collagen gene expression in articular chondrocytes.  An ER66/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 17-E 2 action in chondrocytes.  17-E 2 might be an attractive candidate for cartilage engineering applications.2

Oestrogen and parathyroid hormone alleviate lumbar intervertebral disc degeneration in ovariectomized rats and enhance Wnt/β-catenin pathway activity

“…In addition to the effects discussed above, oestrogen directly promotes collagen metabolism and biochemical function of proteoglycans3536. Though the intervertebral disc is avascular, in view of the fact that nutrients can enter the nucleus pulposus through the endplate, oestrogen and other hormones can potentially also enter the nucleus pulposus and play a direct role in the growth and metabolism of NP cells.…”

The Effect of the Prethanol Extract of <b><i>Trifolium pratense</i></b> Leaves on Interleukin-1β-Induced Cartilage Matrix Degradation in Primary Rat Chondrocytes

“…It is also one of the reasons that OA prevalence is higher in women than in men [Spector et al, 1997;Wluka et al, 2000;Claasen et al, 2008]. Many studies report that phytoestrogen by oral administration exerts a positive effect through upregulation of COL2A1, proteoglycan, and the cartilage oligomeric matrix in menopausal and nonmenopausal OA patients [Seo et al, 2012;Maneix et al, 2014]. In addition to the direct or indirect protective effect of these estrogen-related drugs and modulators (including phytoestrogen) on articular cartilage, subchondral bone, and the surrounding joint tissues including the synovium and muscle, the joint tissues themselves interact with each other, thereby maintaining the organ homeostasis of the joint as a whole, and finally delay joint degeneration [Karsdal et al, 2012;Xiao et al, 2016].…”

Peer Review #1 of "Investigation of the effects of estrogen on skeletal gene expression during zebrafish larval head development (v0.1)"

“…We assessed the expression of a Manuscript to be reviewed (Qu et al, 1999;Joshi, Chang & Hamel, 2006;Lours-Calet et al, 2014) bmp2 (a/b) Induction of bone and cartilage formation + + ? + (Thisse et al, 2001(Thisse et al, , 2004Zhou et al, 2003;Nie, Luukko & Kettunen, 2006;Hu, Colnot & Marcucio, 2008;Yamamoto, Saatcioglu & Matsuda, 2013) col2a1a Extracellular matrix formation in cartilaginous tissues + + + + (Maddox et al;Eames et al, 2010;Maneix et al, 2014) ctsk Bone remodelling and resorption + + + + (Thisse et al, 2004;Troen, 2006;Petrey et al, 2012;Ahi et al, 2014) dlk1…”