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Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

  • Craig M Keenan
  • Andrew J Preston
  • Hazel Sutherland
  • Peter J Wilson
  • Eftychia E Psarelli
  • Trevor F Cox
  • Lakshminarayan R Ranganath
  • Jonathan C Jarvis
  • James A GallagherEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 24)

Abstract

Alkaptonuria (AKU) is an ultrarare autosomal recessive disorder resulting from a deficiency of homogentisate 1,2 dioxygenase (HGD), an enzyme involved in the catabolism of phenylalanine and tyrosine. Loss of HGD function prevents metabolism of homogentisic acid (HGA), leading to increased levels of plasma HGA and urinary excretion. Excess HGA becomes deposited in collagenous tissues and subsequently undergoes polymerisation, principally in the cartilages of loaded joints, in a process known as ochronosis. This results in an early-onset, devastating osteoarthropathy for which there is currently no effective treatment. We recently described the natural history of ochronosis in a murine model of AKU, demonstrating that deposition of ochronotic pigment begins very early in life and accumulates with age. Using this model, we were able to show that lifetime treatment with nitisinone, a potential therapy for AKU, was able to completely prevent deposition of ochronotic pigment. However, although nitisinone has been shown to inhibit ochronotic deposition, whether it can also facilitate removal of existing pigment has not yet been examined. We describe here that midlife administration of nitisinone to AKU mice arrests further deposition of ochronotic pigment in the tibiofemoral joint, but does not result in the clearance of existing pigment. We also demonstrate the dose-dependent response of plasma HGA to nitisinone, highlighting its efficacy for personalised medicine, where dosage can be tailored to the individual AKU patient.

Keywords

Tibial Plateau Tibiofemoral Joint Homogentisic Acid Lifetime Treatment Tyrosinaemia Type 
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.

Supplementary material

346908_1_En_437_MOESM1_ESM.docx (187 kb)
Supplementary Fig. 1. (a) xyz scatter graph showing the location of pigmented chondrons across the tibial articular cartilage of a BALB/c Hgd−/− mouse knee, through 23 serial coronal sections. (b) xyz scatter graph showing the surface of the tibial articular cartilage from a BALB/c Hgd−/− mouse knee through 23 serial sections, with the most anterior and most posterior sections showing the area of entire tibial articular cartilage. Both graphs are 3D representations throughout the anterolateral plane

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Craig M Keenan
    • 1
  • Andrew J Preston
    • 2
  • Hazel Sutherland
    • 1
    • 5
  • Peter J Wilson
    • 1
  • Eftychia E Psarelli
    • 3
  • Trevor F Cox
    • 3
  • Lakshminarayan R Ranganath
    • 1
    • 4
  • Jonathan C Jarvis
    • 5
  • James A Gallagher
    • 1
    Email author
  1. 1.Department of Musculoskeletal Biology, Institute of Ageing and Chronic DiseaseUniversity of LiverpoolLiverpoolUK
  2. 2.Developmental Immunology, Paediatrics, Weatherall Institute of Molecular MedicineUniversity of Oxford, John Radcliffe HospitalOxfordUK
  3. 3.Cancer Research UK Liverpool Cancer Trials UnitUniversity of LiverpoolLiverpoolUK
  4. 4.Department of Clinical Biochemistry and MetabolismRoyal Liverpool University HospitalLiverpoolUK
  5. 5.School of Sport and Exercise SciencesLiverpool John Moores UniversityLiverpoolUK

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