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Investigating the Robustness and Diagnostic Potential of Extracellular Matrix Remodelling Biomarkers in Alkaptonuria

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JIMD Reports, Volume 24

Part of the book series: JIMD Reports ((JIMD,volume 24))

Abstract

Background and aim: Alkaptonuria (AKU) clinical manifestations resemble severe arthritis. The Suitability of Nitisinone in Alkaptonuria 1 (SONIA 1) study is a dose-finding trial for nitisinone treatment of AKU patients. We tested a panel of serum and urinary biomarkers reflecting extracellular matrix remodelling (ECMR) of cartilage, bone and connective tissue in SONIA 1 patients to identify non-invasive and diagnostic biomarkers of tissue turnover in AKU.

Methods: Fasted serum and urine were retrieved from 40 SONIA 1 patients and 44 healthy controls. Established biomarkers of bone remodelling (CTX-I, P1NP, OC), cartilage remodelling (CTX-II, C2M, AGNx1) and inflammation (CRPM) as well as exploratory biomarkers of ECMR (C6M, VCANM, MIM, TIM) were measured at baseline in serum and urine by means of enzyme-linked immunosorbent assays (ELISAs) or automated systems (Elecsys 2010).

Results: The levels of bone resorption (CTX-I) and cartilage degradation (C2M) were elevated in AKU patients as compared to controls (p > 0.0001 and p = 0.03, respectively). Also tissue inflammation (CRPM) was elevated in AKU patients (p = 0.01). In addition all four exploratory biomarkers of ECMR (C6M, VCANM, MIM, TIM) were elevated in AKU patients compared to healthy controls. CTX-II was the only biomarker to be reduced in AKU patients. TIM was the only marker that showed a higher concentration than the normal assay range in AKU patients.

Conclusions: We have identified new potential biomarkers for assessment of cartilage, bone and cardiovascular remodelling in AKU and demonstrated the robustness of the assays used to measure the biomarker concentration in biological fluids.

Competing interests: None declared

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Acknowledgements

This study was funded by the European Union Seventh Framework Programme (project 304985) and by the Danish Research Fund (“Den Danske Forskningsfond”).

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Authors and Affiliations

  1. Nordic Bioscience, Herlev Hovedgade 205, 2730, Herlev, Denmark

    F. Genovese, A. S. Siebuhr, K. Musa, M. A. Karsdal & A. C. Bay-Jensen

  2. Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L69 3GE, UK

    J. A. Gallagher, A. M. Milan & L. R. Ranganath

  3. Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital Trust, Prescot Street, Liverpool, L7 8XP, UK

    A. M. Milan & L. R. Ranganath

  4. National Institute of Rheumatic Diseases, Nabrezie, Ivana Krasku 4, 921 01, Piešťany, Slovakia

    J. Rovensky

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  1. F. Genovese
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Correspondence to F. Genovese .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. Division of Metabolism and Children’s Research Centre, University Children’s Hospital Zuri, Zurich, Switzerland

    Matthias Baumgartner

  3. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  4. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  5. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Verena Peters

Synopsis

Robust assays for non-invasive assessment of extracellular matrix turnover biomarkers can be used to describe the cartilage, bone and cardiovascular remodelling in alkaptonuria patients.

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Conflict of Interests

Federica Genovese is a full-time employee at Nordic Bioscience.

Anne Sofie Siebuhr is a full-time employee at Nordic Bioscience.

Kishwar Musa is a full-time employee at Nordic Bioscience.

Morten Karsdal is a full-time employee and holds shares at Nordic Bioscience.

Anne-Christine Bay-Jensen is a full-time employee and holds shares at Nordic Bioscience.

James Gallagher, Anna Milan, Jozef Rovensky and Lakshminarayan Ranganath declare that they have no conflict of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Details of the Contributions of Individual Authors

Federica Genovese, Anne-Christine Bay-Jensen, Morten Karsdal, Jozef Rovensky and Lakshminarayan Ranganath conceived and designed the study; Kishwar Musa and Anna Milan performed the analysis; Federica Genovese, Anna Milan, Anne Sofie Siebuhr and Anne-Christine Bay-Jensen interpreted the data; Federica Genovese, Anne Sofie Siebuhr, James Gallagher, Anna Milan and Anne-Christine Bay-Jensen drafted the manuscript; and Anne-Christine Bay-Jensen, James Gallagher and Morten Karsdal revised the manuscript critically for important intellectual content.

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Genovese, F. et al. (2015). Investigating the Robustness and Diagnostic Potential of Extracellular Matrix Remodelling Biomarkers in Alkaptonuria. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_430

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  • DOI: https://doi.org/10.1007/8904_2015_430

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  • Print ISBN: 978-3-662-48226-1

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