Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis

Arthritis Rheum. 2010 Jan;62(1):150-8. doi: 10.1002/art.27231.


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.

Conclusion: 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.

MeSH terms

  • Adult
  • Antibodies, Blocking / pharmacology
  • Antibodies, Monoclonal / pharmacology
  • Arthritis, Psoriatic / blood*
  • Arthritis, Psoriatic / physiopathology
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / physiopathology
  • Etanercept
  • Female
  • Health Status
  • Humans
  • Immunoglobulin G / therapeutic use
  • Intercellular Signaling Peptides and Proteins / blood*
  • Intercellular Signaling Peptides and Proteins / physiology
  • Jurkat Cells
  • Male
  • Middle Aged
  • Receptors, Tumor Necrosis Factor / therapeutic use
  • Severity of Illness Index
  • Signal Transduction / drug effects
  • Spondylitis, Ankylosing / blood*
  • Spondylitis, Ankylosing / drug therapy
  • Spondylitis, Ankylosing / physiopathology
  • Tumor Necrosis Factor-alpha / immunology
  • Wnt Proteins / metabolism


  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • DKK1 protein, human
  • Immunoglobulin G
  • Intercellular Signaling Peptides and Proteins
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Wnt Proteins
  • Etanercept