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Ankylosing spondylitis is characterized by an increased turnover of several different metalloproteinase-derived collagen species: a cross-sectional study

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Abstract

Ankylosing spondylitis (AS) is characterized by gradual cementation of the vertebrae, a process that is described by excessive extracellular matrix remodeling. Specific matrix metalloproteinase (MMP)-derived collagen fragments are released to the circulation, and measurement of those might act as biomarkers of ankylosis. The aim of the study was to investigate the diagnostic value of five novel assays measuring different collagen species. Five newly developed ELISAs measuring MMP-degraded collagen fragments in serum of 40 AS patients and 40 age-matched controls were measured: collagen type I (C1M), type II (C2M), type III (C3M), type IV (C4M) and type VI (C6M) as well as the bone formation marker osteocalcin. The levels of the five collagen neoepitopes were significantly higher in AS patients, except for osteocalcin. Cartilage degradation (C2M) was only significantly correlated with the basement membrane (C4M) in the AS patients. In contrast, C3M was significantly correlated with all of the other collagen markers. The highest diagnostic value was achieved when combining the C2M, C3M and C6M markers, AUC 87% (P < 0.0001). Moreover, a combination of the markers correlated with the clinical mSASS score (P = 0.004, R = 0.44). Novel and unique biomarkers of tissue remodeling may provide diagnostic value and aid in understanding of the AS pathology. Each of the biomarkers tells a unique story, and by combining them in a panel there, we found a strong correlation with mSASSS. We speculate that such panel will be a valuable tool for monitoring patients as effect of treatment, for the prediction of responders and for diagnostic purposes.

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Abbreviations

AS:

Ankylosing spondylitis

AUC:

Area under the curve

CO:

Collagen

CRP:

C-reactive protein

ECM:

Extracellular matrix

ESR:

Erythrocyte sedimentation rate

MMP:

Metalloproteinase

OA:

Osteoarthritis

RA:

Rheumatoid arthritis

SpA:

Spondyloarthropathy

References

  1. Karsdal MA, Henriksen K, Leeming DJ, Mitchell P, Duffin K, Barascuk N et al (2009) Biochemical markers and the FDA critical path: how biomarkers may contribute to the understanding of pathophysiology and provide unique and necessary tools for drug development. Biomarkers 14(3):181–202

    Article  PubMed  CAS  Google Scholar 

  2. Sondergaard BC, Henriksen K, Wulf H, Oestergaard S, Schurigt U, Brauer R et al (2006) Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation. Osteoarthr Cartil 14(8):738–748

    Article  PubMed  CAS  Google Scholar 

  3. Tam LS, Gu J, Yu D (2010) Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol 6(7):399–405

    Article  PubMed  Google Scholar 

  4. Braun J, Pincus T (2002) Mortality, course of disease and prognosis of patients with ankylosing spondylitis. Clin Exp Rheumatol 20(6 Suppl 28):S16–S22

    PubMed  CAS  Google Scholar 

  5. Dakwar E, Reddy J, Vale FL, Uribe JS (2008) A review of the pathogenesis of ankylosing spondylitis. Neurosurg Focus 24(1):E2

    Article  PubMed  Google Scholar 

  6. Kumar V, Abbas AK, Fausto N, Aster JC (2010) Tissue renewal, regeneration and repair. In: Robbins, Cotran (eds) Pathologic basis of disease, 8th edn. Elsevier, Philadelphia, pp 79–110

  7. Schuppan D, Ruehl M, Somasundaram R, Hahn EG (2001) Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 21(3):351–372

    Article  PubMed  CAS  Google Scholar 

  8. Lochter A, Bissell MJ (1999) An odyssey from breast to bone: multi-step control of mammary metastases and osteolysis by matrix metalloproteinases. APMIS 107:128–136

    Article  PubMed  CAS  Google Scholar 

  9. Karsdal MA, Madsen SH, Christiansen C, Henriksen K, Fosang AJ, Sondergaard BC (2008) Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity. Arthritis Res Ther 10(3):R63

    Article  PubMed  Google Scholar 

  10. Bay-Jensen AC, Hoegh-Madsen S, Dam E, Henriksen K, Sondergaard BC, Pastoureau P et al (2010) Which elements are involved in reversible and irreversible cartilage degradation in osteoarthritis? Rheumatol Int 30(4):435–442

    Google Scholar 

  11. Zhen EY, Brittain IJ, Laska DA, Mitchell PG, Sumer EU, Karsdal MA et al (2008) Characterization of metalloprotease cleavage products of human articular cartilage. Arthritis Rheum 58(8):2420–2431

    Article  PubMed  CAS  Google Scholar 

  12. Schaller S, Henriksen K, Hoegh-Andersen P, Sondergaard BC, Sumer EU, Tanko LB et al (2005) In vitro, ex vivo, and in vivo methodological approaches for studying therapeutic targets of osteoporosis and degenerative joint diseases: how biomarkers can assist? Assay Drug Dev Technol 3:553–580

    Article  PubMed  CAS  Google Scholar 

  13. Leeming DJ, He Y, Veidal S, Nguyen Q, Larsen D, Koizumi M, Segovia-Silvestre T, Zhang C, Zheng Q, Sun S, Cao Y, Barkholt V, Hägglund P, Bay-Jensen A, Qvist P, Karsdal M (2011) A novel marker for assessment of liver matrix remodeling: an enzyme-linked immunosorbent assay (ELISA) detecting a MMP generated type I collagen neo-epitope (C1M). Biomarkers 16(7):616–628

    Google Scholar 

  14. Bay-Jensen AC, Liu Q, Byrjalsen I, Li Y, Wang J, Pedersen C et al (2011) Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, C. Clin Biochem (Epub ahead of print)

  15. Barascuk N, Veidal SS, Larsen L, Larsen DV, Larsen MR, Wang J et al (2010) A novel assay for extracellular matrix remodeling associated with liver fibrosis: an enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin Biochem (in press)

  16. Rosenquist C, Bonde M, Fledelius C, Qvist P (1994) A simple enzyme-linked immunosorbent assay of human osteocalcin. Clin Chem 40(7):1258–1264

    PubMed  CAS  Google Scholar 

  17. Muntean L, Rojas-Vargas M, Font P, Simon SP, Rednic S, Schiotis R et al (2011) Relative value of the lumbar spine and hip bone mineral density and bone turnover markers in men with ankylosing spondylitis. Clin Rheumatol

  18. Maksymowych WP, Morency N, Wichuk S, Rahman P, Gladman DD, Inman Rd (2010) Multiplex assay of a panel of 58 biomarkers in ankylosing spondylitis: identification of high priority candidates for prediction of structural damage. Ann Rheum Dis 69(Suppl. 3):428

    Google Scholar 

  19. Barascuk N, Veidal SS, Larsen L, Larsen DV, Larsen MR, Wang J et al (2010) A novel assay for extracellular matrix remodeling associated with liver fibrosis: an enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin Biochem

  20. Leeming DJ, Larsen DV, Zhang C, Hi Y, Veidal SS, Nielsen RH et al (2010) Enzyme-linked immunosorbent serum assays (ELISAs) for rat and human N-terminal pro-peptide of collagen type I (PINP)–assessment of corresponding epitopes. Clin Biochem 43(15):1249–1256

    Article  PubMed  CAS  Google Scholar 

  21. Bay-Jensen AC, liu Q, Byrjalsen I, li Y, Wang J, Pedersen C et al (2010) Serum CIIM level in subjects with severe radiographic osteoarthritis; Description of a new metalloproteinase-derived cartilage biomarker. PONE 1 September 2010 (Submitted)

  22. Schett G (2007) Erosive arthritis. Arthritis Res Ther 9(Suppl 1):S2

    Article  PubMed  Google Scholar 

  23. Schett G (2009) Bone formation versus bone resorption in ankylosing spondylitis. Adv Exp Med Biol 649:114–121

    Article  PubMed  CAS  Google Scholar 

  24. Schett G, Teitelbaum SL (2009) Osteoclasts and Arthritis. J Bone Miner Res 24(7):1142–1146

    Article  Google Scholar 

  25. Schett G (2009) Osteoimmunology in rheumatic diseases. Arthritis Res Ther 11(1):210

    Article  PubMed  Google Scholar 

  26. Ruof J, Stucki G (1999) Validity aspects of erythrocyte sedimentation rate and C-reactive protein in ankylosing spondylitis: a literature review. J Rheumatol 26(4):966–970

    PubMed  CAS  Google Scholar 

  27. Spoorenberg A, van der Heijde D, de Klerk E, Dougados M, de Vlam K, Mielants H et al (1999) Relative value of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis. J Rheumatol 26(4):980–984

    PubMed  CAS  Google Scholar 

  28. Maksymowych WP, Dhillon SS, Park R, Salonen D, Inman RD, Lambert RG (2007) Validation of the spondyloarthritis research consortium of Canada magnetic resonance imaging spinal inflammation index: is it necessary to score the entire spine? Arthritis Rheum 57(3):501–507

    Article  PubMed  Google Scholar 

  29. Wanders AJ, Landewe RB, Spoorenberg A, Dougados M, van der Linden LS, Mielants H et al (2004) What is the most appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the Outcome Measures in Rheumatology Clinical Trials filter. Arthritis Rheum 50(8):2622–2632

    Article  PubMed  Google Scholar 

  30. de Vries MK, van Eijk I, van der Horst-Bruinsma IE, Peters MJ, Nurmohamed MT, Dijkmans BA et al (2009) Erythrocyte sedimentation rate, C-reactive protein level, and serum amyloid a protein for patient selection and monitoring of anti-tumor necrosis factor treatment in ankylosing spondylitis. Arthritis Rheum 61(11):1484–1490

    Article  PubMed  Google Scholar 

  31. Gelse K, Poschl E, Aigner T (2003) Collagens–structure, function, and biosynthesis. Adv Drug Deliv Rev 55(12):1531–1546

    Article  PubMed  CAS  Google Scholar 

  32. Bay-Jensen AC, Liu Q, Byrjalsen I, Li Y, Wang J, Pedersen C et al (2011) Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, C. Clin Biochem (Epub ahead of print)

  33. Hudson BG, Reeders ST, Tryggvason K (1993) Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. J Biol Chem 268(35):26033–26036

    PubMed  CAS  Google Scholar 

  34. Kielty CM, Whittaker SP, Grant ME, Shuttleworth CA (1992) Type VI collagen microfibrils: evidence for a structural association with hyaluronan. J Cell Biol 118(4):979–990

    Article  PubMed  CAS  Google Scholar 

  35. Franck H, Meurer T, Hofbauer LC (2004) Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis. J Rheumatol 31(11):2236–2241

    PubMed  CAS  Google Scholar 

  36. Franck H, Meurer T, Hofbauer LC (2004) Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis. J Rheumatol 31(11):2236–2241

    PubMed  CAS  Google Scholar 

  37. Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R et al (2009) Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 60(11):3257–3262

    Article  PubMed  Google Scholar 

  38. Schett G, Rudwaleit M (2010) Can we stop progression of ankylosing spondylitis? Best Pract Res Clin Rheumatol 24(3):363–371

    Article  PubMed  Google Scholar 

  39. Leeming DJ, Larsen DV, Zhang C, Hi Y, Veidal SS, Nielsen RH et al (2010) Enzyme-linked immunosorbent serum assays (ELISAs) for rat and human N-terminal pro-peptide of collagen type I (PINP)–assessment of corresponding epitopes. Clin Biochem 43(15):1249–1256

    Article  PubMed  CAS  Google Scholar 

  40. Bay-Jensen AC, Liu Q, Byrjalsen I, Li Y, Wang J, Pedersen C et al (2011) Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, C. Clin Biochem (Epub ahead of print)

  41. Barascuk N, Veidal SS, Larsen L, Larsen DV, Larsen MR, Wang J et al (2010) A novel assay for extracellular matrix remodeling associated with liver fibrosis: an enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin Biochem

  42. Veidal SS, Karsdal MA, Nawrocki A, Larsen MR, Dai Y, Zheng Q, Hägglund P, Vainer B, Skjøt-Arkil H, Leeming DJ (2011) Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis. Fibrogenesis Tissue Repair 4:22

    Google Scholar 

  43. Veidal SS, Karsdal MA, Vassiliadis E, Nawrocki A, Larsen MR, Nguyen QH, Hägglund P, Luo Y, Zheng Q, Vainer B, Leeming DJ (2011) MMP mediated degradation of type VI collagen is highly associated with liver fibrosis—identification and validation of a novel biochemical marker assay. PLoS One 6(9):e24753

    Google Scholar 

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Acknowledgments

We would like to thank the technicians Maibritt Andersen, Sedi Tavaelee, Lise Larsen, Quoc Hai Trieu Nguyen and Dorthe Vang Larsen of the Nordic Bioscience assay development laboratory, for assisting the development of the novel biomarkers assays presented in the manuscript. The work of Georg Schett was supported by the Deutsche Forschungsgemeinschaft (SPP1468-IMMUNOBONE), the Bundesministerium für Bildung und Forschung (BMBF; ANCYLOSS) and the MASTERSWITCH and IMI projects of the European Union. The work presented in this article has been conducted with unrestricted support from the Danish research fund (Den danske forsknings fond).

Conflict of interest

All, but Arndt Kleyer and George Schett, were employed by Nordic Bioscience while this study was conducted. The biochemical markers presented in the article are for research use only. Morten Karsdal holds stock in Nordic Bioscience. Other authors have no competing interests.

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Authors and Affiliations

  1. Cartilage Biology and Biomarkers, R&D, Nordic Bioscience, Hovedgade 207, 2730, Herlev, Denmark

    Anne C. Bay-Jensen & Morten A. Karsdal

  2. Fibrosis Biology and Biomarkers, Nordic Bioscience, Herlev, Denmark

    Diana J. Leeming & Sanne S. Veidal

  3. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany

    Arndt Kleyer & Georg Schett

Authors
  1. Anne C. Bay-Jensen
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  2. Diana J. Leeming
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  3. Arndt Kleyer
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  6. Morten A. Karsdal
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Correspondence to Anne C. Bay-Jensen.

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Bay-Jensen, A.C., Leeming, D.J., Kleyer, A. et al. Ankylosing spondylitis is characterized by an increased turnover of several different metalloproteinase-derived collagen species: a cross-sectional study. Rheumatol Int 32, 3565–3572 (2012). https://doi.org/10.1007/s00296-011-2237-8

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