ESE-1 (Elf3 in mouse), a novel ETS transcription factor, is expressed predominately in epithelial tissues in physiological conditions. In inflammatory disorders, ESE-1 is expressed in multiple cell types, including chondrocytes, in response to interleukin-1 (IL-1) and other proinflammatory cytokines. Our recent findings indicate that ESE-1 is a critical regulatory factor involved in cartilage loss during osteoarthritis (OA). We have shown that ESE-1 suppresses type II collagen gene (COL2A1) expression by binding to the COL2A1 promoter and by interacting with Sox9 and CBP. Our preliminary data show that ESE-1 also increases matrix metalloproteinase (MMP)-13, a key collagen-degrading enzyme in OA, by binding to ETS/PEA3 sites in the MMP13 promoter and cooperating with Runx2 and AP-1. The absence of MMP-13 protein in the Ese1/Elf3-deficient mouse, and the increased Ese1 expression in the articular cartilage of the cho/+ mouse model of OA compared to wild type mice, further suggests its pivotal role in cartilage degeneration during OA progression. Thus, we hypothesize that ESE-1 is a novel transcriptional regulator of cartilage destruction in OA.
Specific Aim 1 is designed to: Identify the signaling pathways involved in ESE-1 induction and activation by inflammatory cytokines and in ESE1-mediated MMP-13 gene regulation. We will use chondrocyte culture models to characterize: (a) the signaling and transcriptional mechanisms involved in ESE-1 induction by different inflammatory stimuli;(b) the regulation of MMP-13 promoter activity via functional ETS-binding motifs responsive to ESE-1, as well as potential contributions of other ETS factors, Runx2 and AP-1;and (c) the structural features and phosphorylation sites that determine ESE-1 activity.
Specific Aim 2 will: Determine whether Ese1/Elf3 deficiency protects against or attenuates cartilage loss in surgical and genetic mouse models of OA. We will use Ese1/Elf3-deficient mice to examine whether ablation of ESE- protects against cartilage damage induced by biomechanical challenge or by a genetically abnormal matrix in the Cho/+ mouse model that develops a spontaneous form of agedependent OA.
In Specific Aim 3 we will: Determine the effects of ESE-1 overexpression on onset and progression of OA in mouse knee joints due to aging and surgical OA. We will generate Tet-off-inducible Ese1 transgenic mice to determine whether ESE-1 overexpression, by itself, initiates cartilage degeneration or accelerates surgically induced OA. Deciphering the mechanism of action of ESE-1 by these in vivo and in vitro approaches will enable us to identify novel therapeutic strategies to retard cartilage matrix degeneration during OA and aging. Project Description
Since the causes of osteoarthritis (OA) and its progression are unknown, current therapies can do no more than ameliorate the symptoms. Since our recent findings point to a pivotal role for a novel transcription factor, ESE-1, as an important regulator of cartilage degeneration in OA, we will examine the mechanisms by which ESE-1 is activated and regulates expression of a critical cartilage-degrading enzyme, matrix metalloproteinase-13 and make use of ESE-1 knockout and conditional transgenic mice to determine its role in non-genetic experimentally-induced (surgical) OA and a genetic model of spontaneous OA during aging. These in vivo and in vitro approaches will provide rationale for developing novel targeted therapeutic intervention against OA progression due to trauma and aging.
