Abstract 43

ABSTRACT - INVITED SPEAKERS
Which ADAMTS enzyme is the major aggrecanase?
Studies with ADAMTS-4 and ADAMTS-5 deficient mice

Amanda J Fosang, Heather Stanton, Suzanne B. Golub, Charlotte J. East, Fraser Rogerson

Aggrecan is the major proteoglycan in cartilage and it endows this tissue with its unique capacity to bear load and resist compression. In arthritic cartilage, aggrecan is degraded by one or more "aggrecanases" that are members of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) family of zincdependent proteinases. Although ADAMTS-1, -8 and -9 have weak aggrecan degrading activity in vitro, they are not thought to be the primary aggrecanases because aggrecanolysis is not protected in ADAMTS-1 null mice with experimental arthritis, and cleavage by ADAMTS-8 and -9 is significantly less efficient than cleavage by ADAMTS-4 or -5. ADAMTS-9 has not been detected in adult human cartilage. Conversely, there is good evidence to suggest that ADAMTS-4 and -5 are the primary aggrecanases. ADAMTS-5 is expressed constitutively in cartilage, synovium and joint capsule and ADAMTS-4 is induced by catabolic cytokines in cartilage and synovium. Immunoprecipitation of conditioned media from interleukin- 1-stimulated bovine cartilage with anti-ADAMTS-4 and anti-ADAMTS-5 antibodies inhibits aggrecanase activity by 75% and 15% respectively. However, the relative importance of these two enzymes in cartilage pathology is not known. In order to resolve this point, we have generated mice deficient in either ADAMTS-4, or ADAMTS-5 catalytic activity, and investigated aggrecan degradation in vitro and in vivo.

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