title: Cartilage biomarkers in the osteoarthropathy of alkaptonuria reveal low turnover and accelerated ageing.
abstract: Alkaptonuria (AKU) is a rare autosomal recessive disease resulting from a single enzyme deficiency in tyrosine metabolism. As a result, homogentisic acid cannot be metabolized, causing systemic increases. Over time, homogentisic acid polymerizes and deposits in collagenous tissues, leading to ochronosis. Typically, this occurs in joint cartilages, leading to an early onset, rapidly progressing osteoarthropathy. The aim of this study was to examine tissue turnover in cartilage affected by ochronosis and its role in disease initiation and progression.
  
  
  
  With informed patient consent, hip and knee cartilages were obtained at surgery for arthropathy due to AKU (n = 6; 2 knees/4 hips) and OA (n = 12; 5 knees/7 hips); healthy non-arthritic (non-OA n = 6; 1 knee/5 hips) cartilages were obtained as waste from trauma surgery. We measured cartilage concentrations (normalized to dry weight) of racemized aspartate, GAG, COMP and deamidated COMP (D-COMP). Unpaired AKU, OA and non-OA samples were compared by non-parametric Mann-Whitney U test.
  
  
  
  Despite more extractable total protein being obtained from AKU cartilage than from OA or non-OA cartilage, there was significantly less extractable GAG, COMP and D-COMP in AKU samples compared with OA and non-OA comparators. Racemized Asx (aspartate and asparagine) was significantly enriched in AKU cartilage compared with in OA cartilage.
  
  
  
  These novel data represent the first examination of cartilage matrix components in a sample of patients with AKU, representing almost 10% of the known UK alkaptonuric population. Compared with OA and non-OA, AKU cartilage demonstrates a very low turnover state and has low levels of extractable matrix proteins.
authors.affiliation: Lancaster Medical School, Faculty of Health & Medicine, Lancaster University, Lancaster, UK a.m.taylor@lancs.ac.uk.|Department of Medicine, Duke University School of Medicine, Duke Molecular Physiology Institute.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hsueh
authors.affiliation: Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Lakshminarayan R
authors.initials: LR
authors.lastname: Ranganath
authors.affiliation: Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Gallagher
authors.affiliation: Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Jane P
authors.initials: JP
authors.lastname: Dillon
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke Molecular Physiology Institute.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Huebner
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke Molecular Physiology Institute.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Catterall
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke Molecular Physiology Institute.|Department of Pathology, Duke University School of Medicine, Durham, NC, USA.|Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Kraus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000474:Alkaptonuria / Q000378:metabolism*; D001224:Aspartic Acid / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006621:Hip Joint; D006801:Humans; D007592:Joint Diseases / Q000378:metabolism*; D007719:Knee Joint; D008297:Male; D008875:Middle Aged; D009794:Ochronosis / Q000378:metabolism*; D015207:Osteoarthritis, Hip / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D064236:Cartilage Oligomeric Matrix Protein; D006025:Glycosaminoglycans; D001224:Aspartic Acid
keywords: ageing; alkaptonuria; biomarkers; cartilage oligomeric matrix protein; glycosaminoglycan; ochronosis; osteoarthritis; racemization