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Laboratory of Cartilage Biology

Research Description

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.

We have used several strategies for identifying and characterizing mediators involved in the pathogenesis of osteoarthritis (OA), including culture models of primary human and mouse chondrocytes and cell lines, mouse models, and human cartilage samples. Human cartilage is a complex tissue of matrix proteins that varies from superficial to deep layers and from loaded to unloaded zones. During OA development the normally quiescent chondrocytes with low matrix turnover undergo phenotypic modulation resulting in matrix destruction and abnormal repair.

We have identified new genes, not known previously to act in cartilage, including growth arrest and DNA damage (GADD)-45b and the ETS transcription factor, ESE1/ELF3, induced in chondrocytes by bone morphogenetic protein (BMP)-2 and inflammatory cytokines, respectively. Both GADD45b and ESE1/ELF3 are induced by NF-kB and in turn, upregulate matrix metalloproteinase (MMP)-13 and suppress type II collagen gene (COL2A1) gene expression. A microarray study to compare IL-1b and BMP-2-induced genes resulted in the discovery of a novel role for GADD45b, an anti-apoptotic factor during genotoxic stress and cell cycle arrest, as a mediator of MMP-13 and Col10a1 gene expression during hypertrophic differentiation. Since GADD45b is present in quiescent chondrocytes in normal cartilage and in early OA cartilage at sites peripheral to the lesion in chondrocyte clusters and in deep zone chondrocytes, it may promote chondrocyte survival, while promoting hypertrophy during tidemark advancement.

Current studies involve both in vitro analysis of signaling and transcriptional mechanisms that regulate the expression and activities of GADD45b and ESE-1 and in vivo analysis of the consequences of knockout and transgenic overexpression of these genes in mouse models, using surgical OA (good matrix with abnormal loading) and genetic models with OA-like pathology (bad matrix with normal loading) during aging.

In further studies, we are examining the epigenetic regulation of MMP-13 and using proteomics and genomics approaches to map the signaling networks and microRNA targets that impact on gene expression programs during the onset and progression of OA. These studies may to lead to identification of critical targets for therapy to block cartilage damage and promote effective cartilage repair.