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The chondrocyte is solely responsible for synthesis and maintenance of the resilient articular cartilage matrix that gives this load-bearing tissue its mechanical integrity. When the differentiated cell phenotype is lost, the matrix becomes compromised and cartilage function begins to fail. We have recently shown that hypoxia promotes the differentiated phenotype through hypoxia-inducible factor 2alpha (HIF-2alpha)-mediated SOX9 induction of the main matrix genes. However, to date, only a few genes have been shown to be SOX9 targets, while little is known about SOX9-independent regulators. We therefore performed a detailed microarray study to address these issues. Analysis involved 35 arrays on chondrocytes obtained from seven healthy, non-elderly human cartilage samples. Genes were selected that were down-regulated with serial passage in culture (as this causes loss of the differentiated phenotype) and subsequently up-regulated in hypoxia. The importance of key findings was further probed using the technique of RNA interference on these human articular chondrocytes. Our results show that hypoxia has a broader beneficial effect on the chondrocyte phenotype than has been previously described. Of special note, we report new hypoxia-inducible and SOX9-regulated genes, Gdf10 and Chm-I. In addition, Mig6 and InhbA were induced by hypoxia, predominantly via HIF-2alpha, but were not regulated by SOX9. Therefore, hypoxia, and more specifically HIF-2alpha, promotes both SOX9-dependent and -independent factors important for cartilage homeostasis. HIF-2alpha may therefore represent a new and promising therapeutic target for cartilage repair.

Original publication

DOI

10.1074/jbc.m707729200

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

02/2008

Volume

283

Pages

4778 - 4786

Addresses

Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, London W6 8LH, United Kingdom.

Keywords

Cartilage, Articular, Cells, Cultured, Extracellular Matrix, Chondrocytes, Humans, Inhibin-beta Subunits, Intercellular Signaling Peptides and Proteins, Bone Morphogenetic Proteins, High Mobility Group Proteins, Transcription Factors, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Cell Differentiation, Cell Hypoxia, Up-Regulation, Adolescent, Adult, Middle Aged, Child, Female, Male, Basic Helix-Loop-Helix Transcription Factors, Bone Morphogenetic Protein 3, Growth Differentiation Factor 10, SOX9 Transcription Factor