Osteoarthritis and Cartilage
Volume 18, Issue 9 , Pages 1150-1158 , September 2010

Development of a novel clinical biomarker assay to detect and quantify aggrecanase-generated aggrecan fragments in human synovial fluid, serum and urine

  • C.A. Swearingen

      Affiliations

    • Musculoskeletal Research, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
    • These authors contributed equally to this work.
  • ,
  • J.W. Carpenter

      Affiliations

    • Integrative Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
    • These authors contributed equally to this work.
  • ,
  • R. Siegel

      Affiliations

    • Integrative Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • I.J. Brittain

      Affiliations

    • Integrative Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • J. Dotzlaf

      Affiliations

    • Integrative Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • T.B. Durham

      Affiliations

    • Discovery Chemistry, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • J.L. Toth

      Affiliations

    • Discovery Chemistry, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • D.A. Laska

      Affiliations

    • Integrative Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • J. Marimuthu

      Affiliations

    • Discovery Chemistry, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • C. Liu

      Affiliations

    • Discovery Chemistry, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • D.P. Brown

      Affiliations

    • Integrative Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • Q.L. Carter

      Affiliations

    • Integrative Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • M.R. Wiley

      Affiliations

    • Discovery Chemistry, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • K.L. Duffin

      Affiliations

    • Integrative Biology, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • P.G. Mitchell

      Affiliations

    • Musculoskeletal Research, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
  • ,
  • K. Thirunavukkarasu

      Affiliations

    • Musculoskeletal Research, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA
    • Corresponding Author InformationAddress correspondence and reprint requests to: Kannan Thirunavukkarasu, Drop Code 0403, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285.

Received 7 November 2009 ,Accepted 10 June 2010.

References 

  1. Zeng W, Corcoran C, Collins-Racie L, LaVallie E, Yang Z, Morris E, et al. Comparative aggrecanolytic activities of ADAMTS-7, -9, -10, -16 & -18 versus ADAMTS-4 & -5. Trans Orthop Res Soc. 2005;abstract #1706
  2. Glasson SS, Askew R, Sheppard B, Carito BA, Blanchet T, Ma HL, et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum. 2004;50:2547–2558
  3. Glasson S, Askew R, Sheppard B, Carito B, Blanchet T, Ma H, et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature. 2005;434:644–648
  4. Malfait AM, Liu RQ, Ijiri K, Komiya S, Tortorella MD. Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. J Biol Chem. 2002;277:22201–22208
  5. Stanton H, Rogerson F, East C, Golub S, Lawlor K, Meeker C, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434:648–652
  6. Majumdar MK, Askew R, Schelling S, Stedman N, Blanchet T, Hopkins B, et al. Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis. Arthritis Rheum. 2007;56:3670–3674
  7. Fushimi K, Troeberg L, Nakamura H, Lim NH, Nagase H. Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activity. J Biol Chem. 2008;283:6706–6716
  8. Song RH, Tortorella MD, Malfait AM, Alston JT, Yang Z, Arner EC, et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum. 2007;56:575–585
  9. Sandy JD, Thompson V, Doege K, Verscharen C. The intermediates of aggrecanase-dependent cleavage of aggrecan in rat chondrosarcoma cells treated with interleukin-1. Biochem J. 2000;351(Pt 1):161–166
  10. Tortorella MD, Pratta M, Liu RQ, Austin J, Ross OH, Abbaszade I, et al. Sites of aggrecan cleavage by recombinant human aggrecanase-1 (ADAMTS-4). J Biol Chem. 2000;275(24):18566–18573
  11. Sandy JD, Flannery CR, Neame PJ, Lohmander LS. The structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain. J Clin Invest. 1992;89:1512–1516
  12. Little CB, Meeker CT, Golub SB, Lawlor KE, Farmer PJ, Smith SM, et al. Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. J Clin Invest. 2007;117:1627–1636
  13. Lohmander LS, Neame PJ, Sandy JD. The structure of aggrecan fragments in human synovial fluid. Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis. Arthritis Rheum. 1993;36:1214–1222
  14. Larsson S, Lohmander LS, Struglics A. Synovial fluid level of aggrecan ARGS fragments is a more sensitive marker of joint disease than glycosaminoglycan or aggrecan levels: a cross-sectional study. Arthritis Res Ther. 2009;11:R92
  15. Moller HJ, Larsen FS, Ingemann-Hansen T, Poulsen JH. ELISA for the core protein of the cartilage large aggregating proteoglycan, aggrecan: comparison with the concentrations of immunogenic keratan sulphate in synovial fluid, serum and urine. Clin Chim Acta. 1994;225:43–55
  16. Rousseau JC, Sumer EU, Hein G, Sondergaard BC, Madsen SH, Pedersen C, et al. Patients with rheumatoid arthritis have an altered circulatory aggrecan profile. BMC Musculoskelet Disord. 2008;9:74
  17. Pratta MA, Su JL, Leesnitzer MA, Struglics A, Larsson S, Lohmander LS, et al. Development and characterization of a highly specific and sensitive sandwich ELISA for detection of aggrecanase-generated aggrecan fragments. Osteoarthritis & Cartilage. 2006;14:702–713
  18. Hughes CE, Caterson B, Fosang AJ, Roughley PJ, Mort JS. Monoclonal antibodies that specifically recognize neoepitope sequences generated by ‘aggrecanase’ and matrix metalloproteinase cleavage of aggrecan: application to catabolism in situ and in vitro. Biochem J. 1995;305(Pt 3):799–804
  19. Boder ET, Wittrup KD. Yeast surface display for screening combinatorial polypeptide libraries. Nat Biotechnol. 1997;15:553–557
  20. Hanes J, Plückthun A. In vitro selection and evolution of functional proteins by using ribosome display. Proc Natl Acad Sci U S A. 1997;94:4937–4942
  21. Parmley SF, Smith GP. Antibody-selectable filamentous fd phage vectors: affinity purification of target genes. Gene. 1988;73:305–318
  22. Siegel RW. Antibody affinity optimization using yeast cell surface display. Methods Mol Biol. 2009;504:351–383
  23. Gietz RD, Woods RA. Yeast transformation by the LiAc/SS Carrier DNA/PEG method. Methods Mol Biol. 2006;313:107–120
  24. Orr-Weaver TL, Szostak JW, Rothstein RJ. Genetic applications of yeast transformation with linear and gapped plasmids. Methods Enzymol. 1983;101:228–245
  25. Chao G, Lau WL, Hackel BJ, Sazinsky SL, Lippow SM, Wittrup KD. Isolating and engineering human antibodies using yeast surface display. Nat Protoc. 2006;1:755–768
  26. Feldhaus M, Siegel R. Flow cytometric screening of yeast surface display libraries. Meth Mol Biol Clifton, NJ. 2004;263:311–332
  27. Mitchell PG, Yocum SA, Lopresti-Morrow LL, Tobiassen LM, Bliven M, Otterness I, et al. Characterization of the cartilage protective activity of a dual inhibitor of matrix metalloproteinases and ADAMTS-4. Trans Orthop Res Soc. 2003;abstract #703
  28. Noe MC, Natarajan V, Snow SL, Wolf-Gouveia LA, Mitchell PG, Lopresti-Morrow L, et al. Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13. Bioorg Med Chem Lett. 2005;15:3385–3388
  29. Mercuri FA, Doege KJ, Arner EC, Pratta MA, Last K, Fosang AJ. Recombinant human aggrecan G1-G2 exhibits native binding properties and substrate specificity for matrix metalloproteinases and aggrecanase. J Biol Chem. 1999;274(45):32387–32395
  30. Perkins SJ, Nealis AS, Dudhia J, Hardingham TE. Immunoglobulin fold and tandem repeat structures in proteoglycan N-terminal domains and link protein. J Mol Biol. 1989;206:737–753
  31. Flannery CR, Little CB, Caterson B. Molecular cloning and sequence analysis of the aggrecan interglobular domain from porcine, equine, bovine and ovine cartilage: comparison of proteinase-susceptible regions and sites of keratan sulfate substitution. Matrix Biol. 1998;16:507–511

PII: S1063-4584(10)00214-1

doi: 10.1016/j.joca.2010.06.011

Osteoarthritis and Cartilage
Volume 18, Issue 9 , Pages 1150-1158 , September 2010