Transcriptional Regulation of Chondrocytes in Osteoarthritis

Mary B. Goldring, PhD

Scope

Proteins produced in response to excessive mechanical loading and inflammation in joints not only stimulate the production of enzymes that break down the cartilage but also impair the ability of the chondrocyte, the unique cell type in adult cartilage, to repair the damage. To study the regulation of gene expression by inflammatory and destructive cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-a), cell culture models of primary chondrocytes isolated from cartilage retrieved from patients undergoing joint surgery and human chondrocyte cell lines developed in this laboratory are used to analyze the signaling pathways and transcription factors that target type II collagen (COL2A1), matrix metalloproteinase-13 (MMP-13) and other chondrocyte genes. ESE-1, an epithelial cell-specific ETS transcription factor, is induced by inflammatory cytokines in chondrocytes. Another gene not known previously to act in cartilage, growth arrest and DNA damage (GADD)-45ß, is induced by bone morphogenetic protein (BMP) 2, as shown by DNA microarray analysis. Both GADD45ß and ESE-1 suppress COL2A1 and upregulate MMP-13 gene expression. Both genes are upregulated in mouse models of osteoarthritis due to deficient expression of cartilage-specific collagen genes and in human osteoarthritic cartilage. Current studies involve in vitro analysis of signaling and transcriptional mechanisms that regulate the expression and activities of GADD45 ß and ESE-1 and in vivo analysis of the consequences of knockout and transgenic overexpression of these genes in mouse models of defective skeletal development and osteoarthritis. Since degradation and defective repair of cartilage matrix are major features accounting for the loss of function of articular cartilage in osteoarthritis, these studies are expected to provide understanding of the critical signals involved in cartilage homeostasis and pathogenesis and to lead to the development of targeted therapies that both block cartilage damage and promote effective cartilage repair.

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