title: Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone.
abstract: BACKGROUND
  Alkaptonuria (AKU) is a rare metabolic disease caused by deficiency of homogentisate 1,2 dioxygenase, an enzyme involved in tyrosine catabolism, resulting in increased circulating homogentisic acid (HGA). Over time HGA is progressively deposited as a polymer (termed ochronotic pigment) in collagenous tissues, especially the cartilages of weight bearing joints, leading to severe joint disease.
  
  
  OBJECTIVE
  To characterise blood biochemistry and arthropathy in the AKU mouse model (Hgd-/-). To examine the therapeutic effect of long-term treatment with nitisinone, a potent inhibitor of the enzyme that produces HGA.
  
  
  METHODS
  Lifetime levels of plasma HGA from AKU mice were measured by high-performance liquid chromatography (HPLC). Histological sections of the knee joint were examined for pigmentation. The effect of nitisinone treatment in both tissues was examined.
  
  
  RESULTS
  Mean (±SE) plasma HGA levels were 3- to 4-fold higher (0.148±0.019 mM) than those recorded in human AKU. Chondrocyte pigmentation within the articular cartilage was first observed at 15 weeks, and found to increase steadily with mouse age. Nitisinone treatment reduced plasma HGA in AKU mice throughout their lifetime, and completely prevented pigment deposition.
  
  
  CONCLUSIONS
  The AKU mouse was established as a model of both the plasma biochemistry of AKU and its associated arthropathy. Early-stage treatment of AKU patients with nitisinone could prevent the development of associated joint arthropathies. The cellular pathology of ochronosis in AKU mice is identical to that observed in early human ochronosis and thus is a model in which the early stages of joint pathology can be studied and novel interventions evaluated.
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, Bone and Joint Research Group, University of Liverpool, , Liverpool, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Preston
authors.forename: Craig M
authors.initials: CM
authors.lastname: Keenan
authors.forename: Hazel
authors.initials: H
authors.lastname: Sutherland
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wilson
authors.forename: Brenda
authors.initials: B
authors.lastname: Wlodarski
authors.forename: Adam M
authors.initials: AM
authors.lastname: Taylor
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Williams
authors.forename: Lakshminarayan R
authors.initials: LR
authors.lastname: Ranganath
authors.forename: James A
authors.initials: JA
authors.lastname: Gallagher
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jarvis
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D000474:Alkaptonuria; D000818:Animals; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D003512:Cyclohexanones / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007592:Joint Diseases / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D007719:Knee Joint / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009579:Nitrobenzoates / Q000494:pharmacology*; D009794:Ochronosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*
chemical_list: D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C077073:nitisinone
keywords: Arthritis; Chondrocytes; Knee Osteoarthritis; Osteoarthritis; Treatment