Aggrecanase, a Target for Arthritis Therapy?

Articular inflammation and enzymatic degradation of cartilage components characterize arthritic disease. Enzymatic destruction of aggrecan, a proteoglycan found in articular cartilage, is one of the early signs of arthritis. Matrix metalloproteinases (MMPs) specifically cleave the aggrecan core protein between amino acid residues, Asn341 and Phe342.1-4 Fragments of aggrecan typically found within synovial fluid of arthritic joints, however, are produced by specific cleavage between Glu373 and Ala374.5-9 Cleavage between these two amino acid residues occurs via an unidentified protein(s) ("aggrecanase").

Tortorella et al.10 have recently purified, cloned, and expressed aggrecanase-1, a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteins.11 The protein structure of aggrecanase-1 consists of a signal sequence (SS), propeptide domain, a catalytic domain (containing a zinc-binding motif similar to that found in MMPs and ADAMs), a disintegrin-like domain, and a COOH-terminal domain with a thrombospondin (Tsp) type I motif (see Figure 1). Activity studies with both purified and recombinant forms of aggrecanase-1 demonstrate cleavage of aggrecan between Glu373 and Ala374. Aggrecanase-1 is unable to cleave MMP-specific substrates. In addition, aggrecanase-1 activity can be inhibited by inhibitors of native bovine aggrecanase (i.e., blocking cleavage of aggrecan at the Glu373-Ala374 bond). Identification of aggrecanase-1 and possibly additional aggrecanase family members may lead tof the development of therapeutics to help prevent or delay the loss of articular cartilage in arthritis.


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