title: Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients.
abstract: OBJECTIVE
  Charcot neuropathy is characterized by bone destruction in a foot leading to deformity, instability, and risk of amputation. Little is known about the pathogenic mechanisms. We hypothesized that the bone-regulating Wnt/β-catenin and RANKL/OPG pathways have a role in Charcot arthropathy.
  
  
  METHODS
  24 consecutive Charcot patients were treated by off-loading, and monitored for 2 years by repeated foot radiography, MRI, and circulating levels of sclerostin, dickkopf-1, Wnt inhibitory factor-1, Wnt ligand-1, OPG, and RANKL. 20 neuropathic diabetic controls and 20 healthy controls served as the reference.
  
  
  RESULTS
  Levels of sclerostin, Dkk-1 and Wnt-1, but not of Wif-1, were significantly lower in Charcot patients than in the diabetic controls at inclusion. Dkk-1 and Wnt-1 levels responded to off-loading by increasing. Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups. OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years. OPG/RANKL ratio was balanced in all groups at inclusion, and it remained balanced in Charcot patients on repeated measurement throughout the study.
  
  
  CONCLUSIONS
  High plasma RANKL and OPG levels at diagnosis of Charcot suggest that there is high bone remodeling activity before gradually normalizing after off-loading treatment. The consistently balanced OPG/RANKL ratio in Charcot patients suggests that there is low-key net bone building activity by this pathway following diagnosis and treatment. Inter-group differences at diagnosis and changes in Wnt signaling following off-loading treatment were sufficiently large to be reflected by systemic levels, indicating that this pathway has a role in bone remodeling and bone repair activity in Charcot patients. This is of particular clinical relevance considering the recent emergence of promising drugs that target this system.
authors: Department of Orthopedic Surgery, CapioLundby Hospital , Göteborg.
authors: Agnetha
authors: A
authors: Folestad
authors: Martin
authors: M
authors: Ålund
authors: Susanne
authors: S
authors: Asteberg
authors: Jesper
authors: J
authors: Fowelin
authors: Ylva
authors: Y
authors: Aurell
authors: Jan
authors: J
authors: Göthlin
authors: Jean
authors: J
authors: Cassuto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000097:blood; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000503:physiopathology*; D001177:Arthropathy, Neurogenic / Q000209:etiology / Q000503:physiopathology*; D015415:Biomarkers / Q000097:blood; D019485:Bone Morphogenetic Proteins / Q000097:blood; D016723:Bone Remodeling / Q000502:physiology; D016022:Case-Control Studies; D003929:Diabetic Neuropathies / Q000150:complications / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D005529:Foot Bones / Q000503:physiopathology*; D033023:Foot Joints / Q000000981:diagnostic imaging / Q000503:physiopathology; D005819:Genetic Markers; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010012:Osteogenesis / Q000502:physiology; D053244:Osteoprotegerin / Q000097:blood / Q000502:physiology*; D011446:Prospective Studies; D053245:RANK Ligand / Q000097:blood / Q000502:physiology*; D011859:Radiography; D012097:Repressor Proteins / Q000097:blood; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000097:blood / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*; D051176:beta Catenin / Q000097:blood / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012097:Repressor Proteins; C422903:SOST protein, human; C485569:WIF1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin