title: Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis.
abstract: OBJECTIVE
  To examine the relationship between osteoarthritis (OA) and type 2 diabetes mellitus (DM).
  
  
  METHODS
  OA cartilage from DM and non-DM patients undergoing knee replacement were stimulated by IL-1β for 24 h and release of interleukin-6 (IL-6) and prostaglandin E2 (PGE2) was measured. Primary cultured murine chondrocytes were stimulated for 24 and 72 h with or without IL-1β (5 ng/mL) under normal-glucose (5.5 mM) or high-glucose (25 mM) conditions. The expression and release of pro-inflammatory mediators (IL-6, cyclooxygenase 2 [COX2]/PGE2) were analyzed by quantitative RT-PCR and ELISA/EIA. Glucose uptake was assessed with ((14)C)-2-deoxyglucose. Reactive oxygen species (ROS) and nitric oxide (NO) production were measured. To analyze the mechanism of IL-1β-induced inflammation, cells were pretreated or treated with inhibitors of glucose transport (cytochalasin B), the polyol pathway (epalrestat), mitochondrial oxidative stress (MitoTEMPO) or nitric oxide synthase (l-NAME).
  
  
  RESULTS
  With IL-1β stimulation, IL-6 and PGE2 release was greater in human DM than non-DM OA cartilage (2.7- and 3-fold, respectively) (P < 0.05). In vitro, with IL-1β stimulation, IL-6 and COX2 mRNA expression, IL-6 and PGE2 release, and ROS and NO production were greater under high-than normal-glucose conditions in cultured chondrocytes. IL-1β-increased IL-6 release was reduced with cytochalasin B, epalrestat, L-NAME or MitoTEMPO treatment (-45%, -62%, -38% and -40%, respectively).
  
  
  CONCLUSIONS
  OA cartilages from DM patients showed increased responsiveness to IL-1β-induced inflammation. Accordingly, high glucose enhanced IL-1β-induced inflammation in cultured chondrocytes via oxidative stress and the polyol pathway. High glucose and diabetes may thus participate in the increased inflammation in OA.
authors.affiliation: Inserm UMRS_938, Centre de Recherche St-Antoine, Sorbonne Université UPMC Univ Paris 06, Paris, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Laiguillon
authors.affiliation: Inserm UMRS_938, Centre de Recherche St-Antoine, Sorbonne Université UPMC Univ Paris 06, Paris, France; Rheumatology Department, Assistance Publique - Hôpitaux de Paris (AP-HP), Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Courties
authors.affiliation: Inserm UMRS_938, Centre de Recherche St-Antoine, Sorbonne Université UPMC Univ Paris 06, Paris, France.
authors.forename: X
authors.initials: X
authors.lastname: Houard
authors.affiliation: Inserm UMRS_938, Centre de Recherche St-Antoine, Sorbonne Université UPMC Univ Paris 06, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Auclair
authors.affiliation: Orthopedic Surgery Department, AP-HP, Sorbonne Université UPMC Univ Paris 06, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Sautet
authors.affiliation: Inserm UMRS_938, Centre de Recherche St-Antoine, Sorbonne Université UPMC Univ Paris 06, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Capeau
authors.affiliation: Inserm UMRS_938, Centre de Recherche St-Antoine, Sorbonne Université UPMC Univ Paris 06, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Fève
authors.affiliation: Inserm UMRS_938, Centre de Recherche St-Antoine, Sorbonne Université UPMC Univ Paris 06, Paris, France; Rheumatology Department, Assistance Publique - Hôpitaux de Paris (AP-HP), Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France. Electronic address: francis.berenbaum@sat.aphp.fr.
authors.forename: F
authors.initials: F
authors.lastname: Berenbaum
authors.affiliation: Inserm UMRS_938, Centre de Recherche St-Antoine, Sorbonne Université UPMC Univ Paris 06, Paris, France; Rheumatology Department, Assistance Publique - Hôpitaux de Paris (AP-HP), Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Sellam
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000209:etiology* / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology; D011108:Polymers / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D010446:Peptide Fragments; D011108:Polymers; C024617:polyol; C052994:interleukin-1beta (163-171); D051546:Cyclooxygenase 2; D005947:Glucose; D015232:Dinoprostone
keywords: Diabetes mellitus; Glucose; Metabolic osteoarthritis; Osteoarthritis; Oxidative stress