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Rees, Alison Jane
Languages: English
Types: Doctoral thesis
Subjects:
The main aggrecan catabolite, found in samples of synovial fluid from patients with arthritis, and released from cartilage explant cultures exposed to IL-1, both have the amino-terminal amino acid sequence 374ARGSV... (human sequence enumeration) corresponding to cleavage at the 'aggrecanase site' within the IGD of aggrecan (Sandy et al., 1992, and Lohmander et al., 1993). Loss of aggrecan is a primary event in the destruction of cartilage in arthritic disease. The Glu373- Ala374 bond ('aggrecanase site') within the IGD of the aggrecan core protein is cleaved by members of the ADAMTS family, including ADAMTS-4 and -5 (Tortorella et al., 1999, Abbaszade et al., 1999, and Sandy et al., 2000). In this investigation the model system of chondrocyte-agarose cultures, pioneered by Aydelotte and Kuettner 1988, was used to study the degradation of aggrecan by ADAMTS-4 and -5 in cartilaginous extracellular matrices. Low molecular weight co-migrating 37kD ADAMTS-4 and -5 isoforms were detected in apparently increased amounts in IL-1 a treated cultures compared to controls. These isoforms were bound by heparin and required de novo protein synthesis in the presence of IL-1 a for their generation. As previously reported, de novo protein synthesis in the presence of IL-1 a was also required for 'IGD aggrecanase activity' (Arner et al., 1998). Heparin bound media fractions from IL- 1a treated cultures possessed 'IGD aggrecanase activity' against exogenous aggrecan, which was inhibited by the amino-terminal region of TIMP-3 and was shown to be due to a 37kD isoform of ADAMTS-4. This implicated low molecular weight isoforms of ADAMTS-4 in the aggrecanolysis detected in the presence of IL-1 a. Carboxy-terminal truncation of furin cleaved ADAMTS-4 has previously been proposed as both an activation mechanism for the enzyme (Pratta et al., 2003, Kashiwagi et al., 2004, Gao et al., 2002, Gao et al., 2004 and Flannery et al., 2002) and a means of deregulation of the enzyme's catalytic activity.( Gao et al., 2002, Gao et al., 2004, and Kashiwagi et al., 2004). Therefore high molecular weight Furin cleaved ADAMTS-4 isoforms may be required to play normal physiological roles, whereas the low molecular weight forms are likely to be the enzyme isoforms involved in the destruction of aggrecan and other proteoglycans in articular cartilage during arthritis.
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