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.

References

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