Described originally as Epithelial Specific ETS (ESE)-1 (Elf3 in mouse), we have found that this novel transcription factor suppresses type II collagen gene (COL2A1) expression by binding to the COL2A1 promoter and interacting with Sox9 and CBP and that ESE-1 immunostaining is increased in superficial and midzone regions of cartilage from patients with osteoarthritis (OA). Our preliminary data show that ESE-1 increases the transcription of matrix metalloproteinase (MMP)-13 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 suggest its pivotal role in de-regulated cartilage remodeling during OA. Thus, we hypothesize that ESE-1 is a critical transcriptional regulator of cartilage remodeling during OA progression.
The Specific Aims are: (1) What are the signaling pathways that induce and activate ESE-1 to regulate MMP-13 and other targets? We will use primary mouse and human chondrocytes and cell lines to characterize the signaling and transcriptional mechanisms involved in the induction and action of ESE-1 in the regulation of MMP13 and other gene targets, including the structure/function relationships that determine ESE-1 actions under basal and inflammatory conditions. (2) Does Ese1/Elf3-deficiency protect against or attenuate cartilage loss in surgical and genetic mouse models of OA, and if so, what are its mechanisms of action? We will employ Ese1/Elf3 knockout mice subjected to non-genetic experimentally induced (surgical) OA and the Cho/+ mouse model of age-dependent OA and map gene expression during onset and progression of OA by sensitive, in situ gene expression analysis and other techniques developed in Aim 1. (3) Does ESE-1 over-expression affect the onset or progression of OA in mouse knee joints due to aging or surgical OA? We will generate Tet-Off-inducible Ese1 transgenic mice to examine whether excess ESE-1, by itself, initiates or accelerates surgically induced OA and reveal if ESE-1-dependent mechanisms correlate with the extent of OA progression. By applying insights from in vitro studies to the analysis of early and late events by ex vivo and in situ approaches in the mouse models, we will gain understanding of molecular events underlying initiation and progression that will lead to the development of novel targeted therapies for OA due to trauma or aging.

Public Health Relevance

Our recent findings point to a critical role for a novel transcription factor, ESE-1, in the regulation of cartilage remodeling in osteoarthritis (OA) and have prompted us to examine the mechanisms by which ESE-1 is activated and regulates expression of the cartilage-degrading enzyme, matrix metalloproteinase-13. Thus, we will make use of ESE-1 knockout and conditional transgenic mice to determine its role in non-genetic experimentally-induced (surgical) OA and in genetically based spontaneous OA during aging by applying insights from in vitro studies to the analysis of early and late events by ex vivo and in situ approaches. These studies will provide understanding of molecular events underlying the initiation and progression and lead to the development of novel targeted therapies for OA due to trauma and aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Williams, John
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Hospital for Special Surgery
New York
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Otero, Miguel; Peng, Haibing; Hachem, Karim El et al. (2017) ELF3 modulates type II collagen gene (COL2A1) transcription in chondrocytes by inhibiting SOX9-CBP/p300-driven histone acetyltransferase activity. Connect Tissue Res 58:15-26
Shimada, Hirofumi; Otero, Miguel; Tsuchimochi, Kaneyuki et al. (2016) CCAAT/enhancer binding protein ? (C/EBP?) regulates the transcription of growth arrest and DNA damage-inducible protein 45 ? (GADD45?) in articular chondrocytes. Pathol Res Pract 212:302-9
Ko, Frank C; Dragomir, Cecilia L; Plumb, Darren A et al. (2016) Progressive cell-mediated changes in articular cartilage and bone in mice are initiated by a single session of controlled cyclic compressive loading. J Orthop Res 34:1941-1949
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Goldring, Mary B; Berenbaum, Francis (2015) Emerging targets in osteoarthritis therapy. Curr Opin Pharmacol 22:51-63
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Olivotto, Eleonora; Otero, Miguel; Marcu, Kenneth B et al. (2015) Pathophysiology of osteoarthritis: canonical NF-?B/IKK?-dependent and kinase-independent effects of IKK? in cartilage degradation and chondrocyte differentiation. RMD Open 1:e000061
Imagawa, Kei; de Andrés, María C; Hashimoto, Ko et al. (2014) Association of reduced type IX collagen gene expression in human osteoarthritic chondrocytes with epigenetic silencing by DNA hypermethylation. Arthritis Rheumatol 66:3040-51
Zhao, Ren; Wang, Aimin; Hall, Katherine C et al. (2014) Lack of ADAM10 in endothelial cells affects osteoclasts at the chondro-osseus junction. J Orthop Res 32:224-30

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