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

  • F. GenoveseEmail author
  • A. S. Siebuhr
  • K. Musa
  • J. A. Gallagher
  • A. M. Milan
  • M. A. Karsdal
  • J. Rovensky
  • A. C. Bay-Jensen
  • L. R. Ranganath
Research Report
Part of the JIMD Reports book series (JIMD, volume 24)


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.


Urine Creatinine Cartilage Degradation Extracellular Matrix Remodelling Homogentisic Acid Cardiovascular Remodelling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • F. Genovese
    • 1
    Email author
  • A. S. Siebuhr
    • 1
  • K. Musa
    • 1
  • J. A. Gallagher
    • 2
  • A. M. Milan
    • 2
    • 3
  • M. A. Karsdal
    • 1
  • J. Rovensky
    • 4
  • A. C. Bay-Jensen
    • 1
  • L. R. Ranganath
    • 2
    • 3
  1. 1.Nordic BioscienceHerlevDenmark
  2. 2.Department of Musculoskeletal Biology, Institute of Ageing and Chronic DiseaseUniversity of LiverpoolLiverpoolUK
  3. 3.Department of Clinical Biochemistry and Metabolic MedicineRoyal Liverpool University Hospital TrustLiverpoolUK
  4. 4.National Institute of Rheumatic DiseasesPiešťanySlovakia

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