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Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis

J P Morko, M Söderström, A-M K Säämänen, H J Salminen, E I Vuorio

Skeletal Research Programme, Department of Medical Biochemistry and Molecular Biology, University of Turku, FIN-20520 Turku, Finland

Correspondence to:
Correspondence to:
Dr E Vuorio
Department of Medical Biochemistry and Molecular Biology, University of Turku, FIN-20520 Turku, Finland; eero.vuorio{at}utu.fi

Objectives: To study the expression of cysteine proteinases, particularly cathepsin K, and their extracellular inhibitor cystatin C in articular cartilage of transgenic Del1 mice which harbour a short deletion mutation in a type II collagen transgene and are predisposed to early onset osteoarthritis.

Methods: Northern analysis was used to measure mRNA levels of cathepsins B, H, K, L, and S, and cystatin C in total RNA extracted from knee joints of Del1 mice, using their non-transgenic litter mates as controls. Immunohistochemistry and morphometry was used to study the distribution of cathepsin K and cystatin C in the knee joints.

Results: Up regulation of cathepsin K mRNA expression was seen in the knee joints of transgenic Del1 mice at the onset of cartilage degeneration. Cathepsin K was found near sites of matrix destruction in articular chondrocytes, particularly in clusters of proliferating cells, and in calcified cartilaginous matrix. In intact articular cartilage of control animals, cathepsin K was only seen in a small number of chondrocytes. Upon aging, control animals also developed osteoarthritis, which was accompanied by increased cathepsin K expression. Cystatin C was mostly localised in and around chondrocytes located in calcified cartilage, with no obvious association with the onset of cartilage degeneration.

Conclusion: The temporospatial distribution of cathepsin K in osteoarthritic cartilage suggests a role for this enzyme in the pathogenesis of osteoarthritis. Because cathepsin K can digest cartilage matrix components it may contribute to the development of osteoarthritic lesions. These data may provide new clues for the development of treatments aimed at preventing cartilage degeneration.

Keywords: cathepsin K; cystatin C; osteoarthritis; synovial tissue; transgenic mice

Abbreviations: MMPs, matrix metalloproteinases; PBS, phosphate buffered saline; SDS, sodium dodecyl sulphate; SSC, saline-sodium citrate

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• Ruettger, A., Schueler, S., Mollenhauer, J. A., Wiederanders, B. (2008). Cathepsins B, K, and L Are Regulated by a Defined Collagen Type II Peptide via Activation of Classical Protein Kinase C and p38 MAP Kinase in Articular Chondrocytes. J. Biol. Chem. 283: 1043-1051 [Abstract] [Full Text]