ESE‐1 is a potent repressor of type II collagen gene (COL2A1) transcription in human chondrocytes

Abstract

The epithelium-specific ETS (ESE)-1 transcription factor is induced in chondrocytes by interleukin-1β (IL-1β). We reported previously that early activation of EGR-1 by IL-1β results in suppression of the proximal COL2A1 promoter activity by displacement of Sp1 from GC boxes. Here we report that ESE-1 is a potent transcriptional suppressor of COL2A1 promoter activity in chondrocytes and accounts for the sustained, NF-κB-dependent inhibition by . Of the ETS factors tested, this response was specific to ESE-1, since ESE-3, which was also induced by IL-1β, suppressed COL2A1 promoter activity only weakly. In contrast, overexpression of ETS-1 increased COL2A1 promoter activity and blocked the inhibition by IL-1β. These responses to ESE-1 and ETS-1 were confirmed using siRNA-ESE1 and siRNA-ETS1. In transient cotransfections, the inhibitory responses to ESE-1 and IL-1β colocalized in the -577/-132 bp promoter region, ESE-1 bound specifically to tandem ETS sites at 403/ 381 bp, and IL-1-induced binding of ESE-1 to the COL2A1 promoter was confirmed in vivo by ChIP. Our results indicate that ESE-1 serves a potent repressor function by interacting with at least two sites in the COL2A1 promoter. However, the endogenous response may depend upon the balance of other ETS factors such as ETS-1, and other IL-1-induced factors, including EGR-1 at any given time. Intracellular ESE-1 staining in chondrocytes in cartilage from patients with osteoarthritis (OA), but not in normal cartilage, further suggests a fundamental role for ESE-1 in cartilage degeneration and suppression of repair.The chondrocyte is a specialized mesenchymal cell that synthesizes matrix proteins responsible for the tensile strength and resistance to mechanical loading of the articular cartilage (Poole, 2005). In adult articular cartilage, the chondrocytes maintain a low turnover rate of replacement of cartilage matrix proteins. Collagen turnover has been estimated to occur with a half-life of greater than 100 years, whereas the glycosaminoglycan constituents on the aggrecan core protein are more readily replaced and the half-life of aggrecan subfractions is in the range of 3-24 years. Nevertheless, chondrocytes in vivo respond to NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript structural changes in the surrounding cartilage matrix as occurs during the initial stages of osteoarthritis (OA) when increased cell proliferation and synthesis of matrix proteins, proteinases, and cytokines are observed. The early changes in synthetic activity are viewed as an attempt to regenerate the matrix with cartilage-specific components, including types II, IX, and XI collagens and aggrecan, and the presence of collagens not normally found in adult articular cartilage is evidence of phenotypic modulation (Sandell and Aigner, 2001). Genomic and proteomic analyses of global gene expression cartilage have confirmed the increased levels of type II collagen (COL2A1) mRNA and protein in OA cartilage (Bau et al., 2002;Hermansson et al., 2004), possibly ...

CCAAT/Enhancer-binding Protein β Regulates the Repression of Type II Collagen Expression during the Differentiation from Proliferative to Hypertrophic Chondrocytes

“…It was also reported that Egr-1 inhibited interactions between CBP, Sp1, and TATA-binding proteins by interfering with Sp1 binding to the COL2A1 proximal promoter (37). ESE-1 was also reported to repress COL2A1 by Egr-1 through binding to the COL2A1 promoter (38). In Col2a1 regulation by C/EBP␤, C/EBP␤ may also interact with these co-factors, consequently inhibiting initiation of mRNA transcription in response to the inflammatory signal.…”

Multiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease

“…Interestingly, an induction of ESE-1 by IL-1b was found to occur in human chondrocytes, with ESE-1 functioning as a potent transcriptional suppressor of promoter activity for the type II collagen (COL2A1) gene and accounting for the sustained, NF-kB-dependent inhibition of COL2A1 expression by IL-1b. 68 Moreover, intracellular staining for ESE-1 was observed in chondrocytes from patients with osteoarthritis, but not in normal cartilage, suggesting a fundamental role for ESE-1 in cartilage degeneration and suppression of repair. 68 Substantial evidence for the involvement of ESE-1 in vascular inflammation has also been provided from many different studies.…”

“…68 Moreover, intracellular staining for ESE-1 was observed in chondrocytes from patients with osteoarthritis, but not in normal cartilage, suggesting a fundamental role for ESE-1 in cartilage degeneration and suppression of repair. 68 Substantial evidence for the involvement of ESE-1 in vascular inflammation has also been provided from many different studies. For instance, ESE-1 has been shown to interact with the p50 subunit of NF-kB during the regulation of transcription of the inducible nitric-oxide synthase (NOS2) gene.…”

Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells

“…Members of the Ets family that are located in the collagen promoter region are believed to be associated with collagen gene expression (35,40). Several ECM genes, including type I colla- gen, are regulated by Ets-1 (61).…”