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Differential expression patterns of matrix metalloproteinases and their inhibitors during development of osteoarthritis in a transgenic mouse model

H J Salminen¹, A-M K Säämänen¹, M N Vankemmelbeke², P K Auho¹, M P Perälä¹, E I Vuorio¹

¹ Skeletal Research Programme, Departments of Medical Biochemistry and Molecular Biology, and Surgery, University of Turku, FIN-20520 Turku, Finland
² Institute for Bone and Joint Medicine, Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK

Correspondence to:
Correspondence to:
Dr E Vuorio, University of Turku, Department of Medical Biochemistry and Molecular Biology , Kiinamyllynkatu 10, FIN-20520 Turku, Finland;
Eero.Vuorio{at}utu.fi

Objective: To characterise the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during degeneration of articular cartilage in a transgenic Del1 mouse model for osteoarthritis.

Methods: Northern analysis was used to measure mRNA levels of MMP-2, -3, -8, -9, -13, and -14, and TIMP-1, -2, and -3 in total RNA extracted from knee joints of transgenic Del1 mice, harbouring a 15 amino acid deletion in the triple helical domain of the 1(II) collagen chain, using their non-transgenic littermates as controls. Immunohistochemistry was used to study the presence of cleavage products (neoepitopes) of type II collagen, and the distribution of MMP-13 and TIMP-1 in degenerating cartilage.

Results: Each of the MMP and TIMP mRNAs analysed exhibited distinct expression patterns during development and osteoarthritic degeneration of the knee joint. The most striking change was up regulation of MMP-13 mRNA expression in the knee joints of Del1 mice at the onset of cartilage degeneration. However, the strongest immunostaining for MMP-13 and its inhibitor TIMP-1 was not seen in the degenerating articular cartilage but in synovial tissue, deep calcified cartilage, and subchondral bone. The localisation of type II collagen neoepitopes in chondrocytes and their pericellular matrix followed a similar pattern; they were not seen in cartilage fibrillations, but in adjacent unaffected cartilage.

Conclusion: The primary localisation of MMP-13 and TIMP-1 in hyperplastic synovial tissue, subchondral bone, and calcified cartilage suggests that up regulation of MMP-13 expression during early degeneration of articular cartilage is a secondary response to cartilage erosion. This interpretation is supported by the distribution of type II collagen neoepitopes. Synovial production of MMP-13 may be related to removal of tissue debris released from articular cartilage. In the deep calcified cartilage and adjacent subchondral bone, MMP-13 probably participates in tissue remodelling.

Keywords: osteoarthritis; transgenic mice; matrix metalloproteinases; type II collagen

Abbreviations: MMPs, matrix metalloproteinases; OA, osteoarthritis; PBS, phosphate buffered saline; RT-PCR, reverse transcription-polymerase chain reaction; TIMP, tissue inhibitor of metalloproteinases

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