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").
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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.
References
- Fosang, A.J. et al. (1991) J. Biol. Chem. 266:15579.
- Flannery, C.R. et al. (1992) J. Biol. Chem. 267:1008.
- Fosang, A.J. et al. (1993) Biochem. J. 295:273.
- Fosang, A.J. et al. (1996) FEBS Lett. 380:17.
- Sandy, J.D. et al. (1991) J. Biol. Chem. 266:8683.
- Leulakis, P. et al. (1992) Biochem. J. 264:589.
- Ilic, M.Z. et al. (1992) Biochem. Biophys. 294:115.
- Sandy, J.D. et al. (1992) J. Clin. Invest. 89:1512.
- Lohmander, L.S. et al. (1993) Arthritis Rheum. 36:1214.
- Tortorella, M.D. et al. (1999) Science 284:1664.
- Yamamoto, S. et al. (1999) Immunology Today 20:278.