title: Iron overload in a murine model of hereditary hemochromatosis is associated with accelerated progression of osteoarthritis under mechanical stress.
abstract: OBJECTIVE
  Hereditary hemochromatosis (HH) is a disease caused by mutations in the Hfe gene characterised by systemic iron overload and associated with an increased prevalence of osteoarthritis (OA) but the role of iron overload in the development of OA is still undefined. To further understand the molecular mechanisms involved we have used a murine model of HH and studied the progression of experimental OA under mechanical stress.
  
  
  METHODS
  OA was surgically induced in the knee joints of 10-week-old C57BL6 (wild-type) mice and Hfe-KO mice. OA progression was assessed using histology, micro CT, gene expression and immunohistochemistry at 8 weeks after surgery.
  
  
  RESULTS
  Hfe-KO mice showed a systemic iron overload and an increased iron accumulation in the knee synovial membrane following surgery. The histological OA score was significantly higher in the Hfe-KO mice at 8 weeks after surgery. Micro CT study of the proximal tibia revealed increased subchondral bone volume and increased trabecular thickness. Gene expression and immunohistochemical analysis showed a significant increase in the expression of matrix metallopeptidase 3 (MMP-3) in the joints of Hfe-KO mice compared with control mice at 8 weeks after surgery.
  
  
  CONCLUSIONS
  HH was associated with an accelerated development of OA in mice. Our findings suggest that synovial iron overload has a definite role in the progression of HH-related OA.
authors.affiliation: Department of Orthopedics, Centro Hospitalar Lisboa Central, Lisboa, Portugal; PhD Program in Medicine, NOVA Medical School, University Nova de Lisboa, Lisbon, Portugal; Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal. Electronic address: antonio.camacho@chlc.min-saude.pt.
authors.forename: A
authors.initials: A
authors.lastname: Camacho
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal; PhD Program in Biomedical Sciences, University of Algarve, Faro, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Simão
authors.affiliation: Inserm 1132, Hôpital Lariboisière, Paris, France; Université Paris Diderot, UFR médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Fédération de Rhumatologie, Paris, France.
authors.forename: H-K
authors.initials: HK
authors.lastname: Ea
authors.affiliation: Inserm 1132, Hôpital Lariboisière, Paris, France; Université Paris Diderot, UFR médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Fédération de Rhumatologie, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Cohen-Solal
authors.affiliation: Inserm 1132, Hôpital Lariboisière, Paris, France; Université Paris Diderot, UFR médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Fédération de Rhumatologie, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Richette
authors.affiliation: Department of Rheumatology, Hospital Egas Moniz, Centro Hospitalar Lisboa Ocidental EPE, Lisbon, Portugal; CEDOC - Chronic Diseases Research Center, NOVA Medical School, University Nova de Lisboa, Lisbon, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Branco
authors.affiliation: Department of Biomedical Sciences and Medicine (DCBM), University of Algarve, Faro, Portugal; Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.
authors.forename: M L
authors.initials: ML
authors.lastname: Cancela
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000502:physiology; D006432:Hemochromatosis / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008592:Menisci, Tibial / Q000601:surgery; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010003:Osteoarthritis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D013314:Stress, Mechanical; D013583:Synovial Membrane / Q000378:metabolism
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D007501:Iron; D019278:Matrix Metalloproteinase 3
keywords: Hereditary hemochromatosis; Iron overload; Mechanical stress; Mouse model; Osteoarthritis