title: Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis.
abstract: OBJECTIVE
  Dkk-1 is an inhibitory molecule that regulates the Wnt pathway, which controls osteoblastogenesis. This study was undertaken to explore the potential role of Dkk-1 in ankylosing spondylitis (AS), a prototypical bone-forming disease.
  
  
  METHODS
  Serum Dkk-1 levels were measured in 45 patients with AS, 45 patients with rheumatoid arthritis (RA), 15 patients with psoriatic arthritis (PsA), and 50 healthy subjects by sandwich enzyme-linked immunosorbent assay (ELISA). A functional ELISA was used to assess the binding of Dkk-1 to its receptor (low-density lipoprotein receptor-related protein 6). Furthermore, we studied the effect of sera from patients with AS and healthy subjects on the activity of the Wnt pathway in the Jurkat T cell model, with and without a neutralizing anti-Dkk-1 monoclonal antibody, by Western immunoblotting.
  
  
  RESULTS
  Serum Dkk-1 levels were significantly increased in patients with AS (mean +/- SEM 2,730 +/- 135.1 pg/ml) as compared with normal subjects (P = 0.040), patients with RA (P = 0.020), and patients with PsA (P = 0.049). Patients with AS receiving anti-tumor necrosis factor alpha (anti-TNFalpha) treatment had significantly higher serum Dkk-1 levels than patients with AS not receiving such treatment (P = 0.007). Patients with AS studied serially prior to and following anti-TNFalpha administration exhibited a significant increase in serum Dkk-1 levels (P = 0.020), in contrast to patients with RA, who exhibited a dramatic decrease (P < 0.001). Jurkat cells treated with serum from AS patients exhibited increased Wnt signaling compared with cells treated with control serum. In that system, Dkk-1 blockade significantly enhanced Wnt signaling in control serum-treated, but not AS serum-treated, Jurkat T cells.
  
  
  CONCLUSIONS
  Our findings indicate that in patients with AS, circulating bone formation-promoting factors functionally prevail. This can be at least partially attributed to decreased Dkk-1-mediated inhibition.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Patras University Hospital, University of Patras, Patras, Greece. jimdaoussis@hotmail.com
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Daoussis
authors.forename: Stamatis-Nick C
authors.initials: SN
authors.lastname: Liossis
authors.forename: Elena E
authors.initials: EE
authors.lastname: Solomou
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tsanaktsi
authors.forename: Konstadina
authors.initials: K
authors.lastname: Bounia
authors.forename: Maria
authors.initials: M
authors.lastname: Karampetsou
authors.forename: Georgios
authors.initials: G
authors.lastname: Yiannopoulos
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Andonopoulos
mesh_terms: D000328:Adult; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015535:Arthritis, Psoriatic / Q000097:blood* / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000503:physiopathology; D000068800:Etanercept; D005260:Female; D006304:Health Status; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000502:physiology; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D013167:Spondylitis, Ankylosing / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; C501126:DKK1 protein, human; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; D000068800:Etanercept