GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes

Tsuchimochi, Kaneyuki; Otero, Miguel; Dragomir, Cecilia; Plumb, Darren A.; Zerbini, Luiz F.; Libermann, Towia A.; Marcu, Kenneth B.; Komiya, Setsuro; Ijiri, Kosei; Goldring, Mary B.

doi:10.1074/jbc.m109.038638

Cited by 44 publications

(46 citation statements)

References 82 publications

(104 reference statements)

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“…Plasmid Construction-The Ϫ1602/ϩ20-MMP13-Luc promoter construct was described previously (30). The MMP13 promoter sequences spanning Ϫ1007/ϩ20 and Ϫ273/ϩ20 bp were prepared by PCR using the pCAT-MMP13 promoter construct as template as described (30).…”

Section: Methodsmentioning

confidence: 99%

“…Expression vectors encoding ELF3, ELF5, EHF, RUNX2, c-Fos, and c-Jun have been described (27,30). Vectors encoding JNK, ERK1/2, p38, MKP1, and the constitutively active MAP2K MKK7, MKK6, and MEK1 were purchased from Addgene and described elsewhere (30).…”

Section: Methodsmentioning

confidence: 99%

“…The MMP13 promoter sequences spanning Ϫ1007/ϩ20 and Ϫ273/ϩ20 bp were prepared by PCR using the pCAT-MMP13 promoter construct as template as described (30). The sense primer for each construct included an artificial SacI site and the antisense primer included an artificial XhoI site.…”

Section: Methodsmentioning

confidence: 99%

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E74-like Factor 3 (ELF3) Impacts on Matrix Metalloproteinase 13 (MMP13) Transcriptional Control in Articular Chondrocytes under Proinflammatory Stress

Otero

Plumb

Tsuchimochi

et al. 2012

Journal of Biological Chemistry

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Matrix metalloproteinase (MMP)-13 has a pivotal, rate-limiting function in cartilage remodeling and degradation due to its specificity for cleaving type II collagen. The proximal MMP13 promoter contains evolutionarily conserved E26 transformation-specific sequence binding sites that are closely flanked by AP-1 and Runx2 binding motifs, and interplay among these and other factors has been implicated in regulation by stress and inflammatory signals. Here we report that ELF3 directly controls MMP13 promoter activity by targeting an E26 transformation-specific sequence binding site at position ؊78 bp and by cooperating with AP-1. In addition, ELF3 binding to the proximal MMP13 promoter is enhanced by IL-1␤ stimulation in chondrocytes, and the IL-1␤-induced MMP13 expression is inhibited in primary human chondrocytes by siRNA-ELF3 knockdown and in chondrocytes from Elf3 ؊/؊ mice. Further, we found that MEK/ERK signaling enhances ELF3-driven MMP13 transactivation and is required for IL-1␤-induced ELF3 binding to the MMP13 promoter, as assessed by chromatin immunoprecipitation. Finally, we show that enhanced levels of ELF3 co-localize with MMP13 protein and activity in human osteoarthritic cartilage. These studies define a novel role for ELF3 as a procatabolic factor that may contribute to cartilage remodeling and degradation by regulating MMP13 gene transcription.The matrix metalloproteinases (MMPs) 3 are a family of enzymes that coordinately degrade components of the extracellular matrix in physiological/normal matrix remodeling processes (1) and in disease states wherein their aberrant and enhanced expression contributes to exacerbated matrix degradation (2, 3). Type II collagen is a major constituent of articular cartilage that contributes to its structural and functional properties by conferring tensile strength, and its degradation is the pivotal event that determines the irreversible progression of osteoarthritis (OA), in which articular cartilage is slowly and progressively destroyed (2). OA occurs in conjunction with changes in the synovium and subchondral bone that are associated with dysregulated chondrocyte physiology exemplified in part by the abnormal expression of catabolic and anabolic gene products (2). In this context, proinflammatory cytokines have been shown to trigger a diverse array of intracellular signaling pathways leading to the overexpression of a variety of matrix-degrading enzymes, including MMPs (2).Because collagen degradation is mediated almost exclusively by MMPs, those with higher collagenolytic activity (collagenases) are the rate-limiting, major players in irreversible cartilage destruction (4), and MMP13 (collagenase 3) plays a very prominent role here. MMP13 preferentially and more potently cleaves type II collagen compared with other collagenases (5-7). Moreover, MMP13 levels and activity are enhanced in OA cartilage, associated with degenerative changes and co-localizing with MMP13-specific type II collagen cleavage products, inflammatory cytokines, and their receptors (4,8). Furt...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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E74-like Factor 3 (ELF3) Impacts on Matrix Metalloproteinase 13 (MMP13) Transcriptional Control in Articular Chondrocytes under Proinflammatory Stress

Otero

Plumb

Tsuchimochi

et al. 2012

Journal of Biological Chemistry

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“…NFκB signaling strongly induces the expression of transcription factors such as HIF2α [Yang et al 2010] and Elf3 [Otero et al 2012], which in turn bind to and activate MMP13 and other gene promoters (Figure 1). The stress-induced MAPK pathways, including the ERK, c-Jun N-terminal kinase (JNK) and p38 MAPK cascades, coordinate the induction and activation of gene expression through transcription factors such as activator protein 1 (cFos/cJun), ETS, C/EBPβ, and Runx2 [Goldring and Sandell, 2007;Long and Loeser, 2010;Tetsunaga et al 2011;Tsuchimochi et al 2010]. Induction of both ADAMTS4 and 5 requires Runx2 [Tetsunaga et al 2011], and NFκB and HIF2α [Yang et al 2010] mediate ADAMTS4 upregulation, whereas MMP-13 induction requires all three transcription factors.…”

Section: Inflammation and Mechanical Stress In Osteoarthritismentioning

confidence: 99%

Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis

Goldring

2012

Therapeutic Advances in Musculoskeletal

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Chondrogenesis occurs as a result of mesenchymal cell condensation and chondroprogenitor cell differentiation. Following chondrogenesis, the chondrocytes remain as resting cells to form the articular cartilage or undergo proliferation, terminal differentiation to chondrocyte hypertrophy, and apoptosis in a process termed endochondral ossification, whereby the hypertrophic cartilage is replaced by bone. Human adult articular cartilage is a complex tissue of matrix proteins that varies from superficial to deep layers and from loaded to unloaded zones. A major challenge to efforts to repair cartilage by stem cell-based and other tissue-engineering strategies is the inability of the resident chondrocytes to lay down a new matrix with the same properties as it had when it was formed during development. Thus, understanding and comparing the mechanisms of cartilage remodeling during development, osteoarthritis (OA), and aging may lead to more effective strategies for preventing cartilage damage and promoting repair. The pivotal proteinase that marks OA progression is matrix metalloproteinase 13 (MMP-13), the major type II collagen-degrading collagenase, which is regulated by both stress and inflammatory signals. We and other investigators have found that there are common mediators of these processes in human OA cartilage. We also observe temporal and spatial expression of these mediators in early through late stages of OA in mouse models and are analyzing the consequences of knockout or transgenic overexpression of critical genes. Since the chondrocytes in adult human cartilage are normally quiescent and maintain the matrix in a low turnover state, understanding how they undergo phenotypic modulation and promote matrix destruction and abnormal repair in OA may to lead to identification of critical targets for therapy to block cartilage damage and promote effective cartilage repair.

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“…Houvras et al (Houvras and others 2000) found that wild type (wt) BRCA1 bound ATF1, causing transcription of a luciferase reporter gene. Such a finding strongly suggests (Ishiguro, 1997) StAR (Clem, 2005) Thrombospondin 1 (Ghoneim, 2007) Collagen, type X, α1 (Tsuchimochi, 2010) MMP13 (Tsuchimochi, 2010) Cyclin A (van Dam, 2001) Aromatase (Deb, 2006) MMP2 (Song, 2006) COX2 (Subbaramaiah, 2002) Cyclin D1 (Lee, 1999) Maspin (Maekawa, 2008) IFNγ (Xue, 2005) FoxP3 Fibronectin (Yin, 2010) Snail (Yin, 2010) Twist (Yin, 2010) Slug (Yin, 2010) av integrin (Yin, 2010) β6 integrin (Yin, 2010) E-cadherin (Yin, 2010) Increased malignancy Osteocalcin ( www.intechopen.com very few studies have been performed on the role of ATF1 in breast cancer. Important future studies will elucidate the effects of ATF1 on immunity and hormone synthesis in both normal and neoplastic breast cells, as well as its role in breast cancer in vivo.…”

Section: Atf1mentioning

confidence: 99%

The ATF/CREB Family of Transcription Factors in Breast Cancer

Haakenson¹,

Kester²,

Zlobec³

2012

Targeting New Pathways and Cell Death in Breast Cancer

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GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes

Cited by 44 publications

References 82 publications

E74-like Factor 3 (ELF3) Impacts on Matrix Metalloproteinase 13 (MMP13) Transcriptional Control in Articular Chondrocytes under Proinflammatory Stress

E74-like Factor 3 (ELF3) Impacts on Matrix Metalloproteinase 13 (MMP13) Transcriptional Control in Articular Chondrocytes under Proinflammatory Stress

Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis

The ATF/CREB Family of Transcription Factors in Breast Cancer

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