Matrix metalloproteinase digestion of aggrecan in human cartilage tumours

Substantial experimental and clinical evidence suggests that the catabolism of extracellular matrix components is a prerequisite for invasive and metastatic behaviour of solid tumours. Chondrosarcomas are malignant cartilaginous tumours that most commonly arise in bone, and the large aggregating proteoglycan aggrecan is a major component of the extracellular matrix of these tumours. Matrix metalloproteinases (MMPs) have been implicated in tumour invasiveness. The purpose of this study was to determine whether MMPs play a role in aggrecan catabolism in cartilage tumours. In order to detect aggrecan digestion products resulting from in vivo cleavage at the MMP site, protein extracts from human articular cartilage and from various cartilage tumours were analysed by Western blot using an antibody to the FVDIPEN neoepitope generated by MMP cleavage. Examination of cartilage extracts revealed a trend of increasing aggrecan digestion at the MMP site with age. One hyaline chondrosarcoma and three osteochondromas lacked detectable aggrecan fragments with the carboxy terminal FVDIPEN neoepitope. Two osteochondromas gave weak signals. However, all chondrosarcomas with degenerating extracellular matrix or with a myxoid component exhibited strong FVDIPEN immunoreactivity. These results demonstrate that, in contrast to the benign cartilage tumour osteochondroma, human chondrosarcomas contain abundant aggrecan degradation products resulting from cleavage in vivo at the MMP site in the interglobular domain. These data support the concept that MMPs participate in the degradation of extracellular matrix in chondrosarcoma, allowing the neoplastic chondrocytes to escape local confinement, migrate, and invade neighbouring and remote tissues.