The catabolic and proinflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced in the joint tissues, not only contribute to the destruction of cartilage matrix in osteoarthntis and rheumatoid arthritis, but also decrease the synthesis of cartilage-specific matrix proteins, including type II collagen and aggrecan. We have shown in published and preliminary studies that IL-1beta suppresses expression of the type II collagen gene (COL2A1) in chondrocytes at the transcriptional level via multiple signaling pathways. Furthermore, we have found that a novel ETS factor, ESE-1, which is induced by ILi1beta and TNF-alpha, binds to the COL2A1 promoter and directly suppresses its activity, indicating a pivotal role for this transcription factor in regulating COL2A1 gene expression. Our hypothesis is that IL-1beta-induced suppression of COL2A1 gene expression is mediated by ESE-1 as the primary transcriptional regulator and involves multiple signaling pathways and transcription factors that interact directly or indirectly with ESE-1. For these studies, we have developed immortalized human chondrocyte cell lines, which retain chondrocyte-specific phenotype and responses to cytokines.
The Specific Aims will test the hypotheses that: (1) ESE-1 is the primary transcription factor involved in IL-1beta-mediated suppression of the COL2A 1 gene; (2) multiple signaling pathways involving p38 MAPK, JNK, Jak3, IKK/IkappaB and P13K/Akt kinase cascades transduce IL-1beta-induced suppression of COL2A1 gene expression, both directly and indirectly, via ESE-1; (3) ESE-1 serves its repressor function on COL2A1 expression via specific protein-DNA and protein-protein interactions involving other IL-1beta-induced transcription factors and constitutive factors; and (4) ESE-1 suppression of COL2A1 expression results in chondrocyte-dependent inhibition of cartilage matrix synthesis. These studies will permit dissection of the specific signaling pathways and molecular regulatory systems involved in transcriptional regulation of the COL2A1 gene by IL-1beta. These results may also lead to the development of more specific and effective therapeutic approaches for blocking the adverse effects of IL-1beta on cartilage matrix genes and their products in disorders such as OA and RA.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG022021-04
Application #
6918559
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Kohanski, Ronald A
Project Start
2002-08-15
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$340,000
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Goldring, Steven R; Goldring, Mary B (2016) Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol 12:632-644
Holyoak, Derek T; Tian, Ye F; van der Meulen, Marjolein C H et al. (2016) Osteoarthritis: Pathology, Mouse Models, and Nanoparticle Injectable Systems for Targeted Treatment. Ann Biomed Eng 44:2062-75
Culley, Kirsty L; Dragomir, Cecilia L; Chang, Jun et al. (2015) Mouse models of osteoarthritis: surgical model of posttraumatic osteoarthritis induced by destabilization of the medial meniscus. Methods Mol Biol 1226:143-73
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
Goldring, Mary B; Berenbaum, Francis (2015) Emerging targets in osteoarthritis therapy. Curr Opin Pharmacol 22:51-63
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

Showing the most recent 10 out of 95 publications