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The plasma levels of Dickkopf-1 elevated in patients with Juvenile Idiopathic Arthritis

Abstract

Background

To explore the role of two major inhibitors of Wnt signal pathway, Dickkopf-1(DKK-1) and Sclerostin (SOST), in the pathogenesis of juvenile idiopathic arthritis (JIA).

Methods

88 patients with JIA, which including 49 patients with enthesitis-related arthritis (ERA), 21 oligoarthritis (oJIA) and 18 polyarthritis (pJIA), and 36 age-and sex-matched children as healthy controls (HC) were enrolled in this study. The plasma levels of DKK-1 and SOST, measured using commercially available ELISA kits, were analyzed the correlation between the levels of DKK-1/SOST and JIA, and were analyzed in 14 patients with JIA during before and after treatment.

Results

Plasma levels of DKK-1 were significantly higher in the patients with JIA than that in HC, the elevation of DKK-1 level was positively correlated with HLA-B27 positive JIA. DKK-1 levels dropped significantly in patient with JIA after treatment (P < 0.05). There was no significant change in SOST levels among different subtypes of JIA, patients with JIA during before and after treatment, and HC.

Conclusion

It was suggested that the DKK-1 may have a certain correlation with the pathogenesis of JIA, and DKK-1 levels are more closely related to the HLA-B27 positive-ERA.

Impact

  • The abnormally elevated levels of Dickkopf-1 (DKK-1) may be involved in the pathogenesis of juvenile idiopathic arthritis (JIA). DKK-1 levels were more closely related to the HLA-B27 positive-enthesitis-related arthritis (ERA). DKK-1 is an inhibitor of Wnt signaling pathway that promotes osteoblastic new bone formation; it is very rare for pediatric patients with HLA-B27 positive-ERA to manifest typical spondylitis, while sacroiliac arthritis is relatively common, which may be related to the high levels of DKK-1, which is consistent with the early stage of ankylosing spondylitis (AS).

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Fig. 1: Plasma levels of DKK-1 and SOST in patients with different clinical subgroups of JIA and controls.
Fig. 2: The correlation between DKK-1 and SOST with disease activity in JIA patients.
Fig. 3: Changes of DKK-1 and SOST with about 6 months treatment in JIA.

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Data availability

All data generated or analysed during this study are included in this published article.

References

  1. Prakken, B., Albani, S. & Martini, A. Juvenile idiopathic arthritis. Lancet 377, 2138–2149 (2011).

    Article  PubMed  Google Scholar 

  2. Martini, A. et al. Toward new classification criteria for juvenile idiopathic arthritis: first steps, pediatric rheumatology international trials organization international consensus. J. Rheumatol. 46, 190–197 (2019).

    Article  PubMed  Google Scholar 

  3. Clevers, H. & Nusse, R. Wnt/Β-catenin signaling and disease. Cell 149, 1192–1205 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Lecarpentier, Y., Schussler, O., Hébert, J.-L. & Vallée, A. Multiple targets of the canonical Wnt/B-Catenin signaling in cancers. Front. Oncol. 9, 1248 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cici, D., Corrado, A., Rotondo, C. & Cantatore, F. P. Wnt signaling and biological therapy in rheumatoid arthritis and spondyloarthritis. Int J. Mol. Sci. 20, 5552 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang, X. D., Huang, X. F., Yan, Q. R. & Bao, C. D. Aberrant activation of the Wnt/Β-Catenin signaling pathway in lupus nephritis. PLoS One 9, e84852 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sun, W. et al. Sclerostin rather than Dickkopf-1 is associated with msasss but not with disease activity score in patients with ankylosing spondylitis. Clin. Rheumatol. 38, 989–995 (2019).

    Article  PubMed  Google Scholar 

  8. Xie, W., Zhou, L., Li, S., Hui, T. & Chen, D. Wnt/Β-Catenin signaling plays a key role in the development of spondyloarthritis. Ann. N. Y. Acad. Sci. 1364, 25–31 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Singh, A., Gupta, M. K. & Mishra, S. P. Study of correlation of level of expression of wnt signaling pathway inhibitors sclerostin and Dickkopf-1 with disease activity and severity in rheumatoid arthritis patients. Drug Disco. Ther. 13, 22–27 (2019).

    Article  CAS  Google Scholar 

  10. Daoussis, D. et al. Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum. 62, 150–158 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Zhou, Y., Wang, T., Hamilton, J. L. & Chen, D. Wnt/Β-Catenin signaling in osteoarthritis and in other forms of arthritis. Curr. Rheumatol. Rep. 19, 53 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Henderson, J., Pryzborski, S., Stratton, R. & O’Reilly, S. Wnt antagonist Dkk-1 levels in systemic sclerosis are lower in skin but not in blood and are regulated by microrna33a-3p. Exp. Dermatol 30, 162–168 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Karataş, A. et al. Wnt signaling pathway activities may be altered in primary Sjogren’s syndrome. Turk. J. Med. Sci. 51, 2015–2022 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Xue, J. et al. Dickkopf-1 is a biomarker for systemic lupus erythematosus and active lupus nephritis. J. Immunol. Res. 2017, 6861575 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Barut, K., Adrovic, A., Şahin, S. & Kasapçopur, Ö. Juvenile idiopathic arthritis. Balk. Med J. 34, 90–101 (2017).

    Article  Google Scholar 

  16. Kwon, S. R. et al. Dickkopf-1 level is lower in patients with ankylosing spondylitis than in healthy people and is not influenced by anti-tumor necrosis factor therapy. Rheumatol. Int. 32, 2523–2527 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Biton, J., Boissier, M. C. & Bessis, N. Tnfα: activator or inhibitor of regulatory T cells? Jt. Bone Spine 79, 119–123 (2012).

    Article  CAS  Google Scholar 

  18. Heiland, G. R. et al. High level of functional Dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann. Rheum. Dis. 71, 572–574 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Rubio Vargas, R. et al. Association between Serum Dickkopf-1 levels and disease duration in axial spondyloarthritis. Reumatol. Clin. 13, 197–200 (2017).

    Article  PubMed  Google Scholar 

  20. Kerschan-Schindl, K. et al. Rheumatoid arthritis in remission: decreased myostatin and increased serum levels of periostin. Wien. Klin. Wochenschr. 131, 1–7 (2019).

    Article  CAS  PubMed  Google Scholar 

  21. Ma, Y. et al. The serum level of Dickkopf-1 in patients with rheumatoid arthritis: a systematic review and meta-analysis. Int Immunopharmacol. 59, 227–232 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Maeda, K. et al. The regulation of bone metabolism and disorders by Wnt signaling. Int. J. Mol. Sci. 20, 5525 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Choe, J. Y., Hun Kim, J., Park, K. Y., Choi, C. H. & Kim, S. K. Activation of Dickkopf-1 and focal adhesion kinase pathway by tumour necrosis factor α induces enhanced migration of fibroblast-like synoviocytes in rheumatoid arthritis. Rheumatol. (Oxf.) 55, 928–938 (2016).

    Article  CAS  Google Scholar 

  24. Tao, S. S. et al. Dickkopf-1 as a promising therapeutic target for autoimmune diseases. Clin. Immunol. 245, 109156 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Cao, D. et al. [Expression of Plasma Dickkopf-1 in Patients with Rheumatoid Arthritis and Its Correlation with Peripheral Blood T Cell Subsets]. Beijing Da Xue Xue Bao Yi Xue Ban. 53, 255–260 (2020).

  26. Seror, R. et al. Increased Dickkopf-1 in recent-onset rheumatoid arthritis is a new biomarker of structural severity. Data from the ESPOIR cohort. Sci. Rep. 6, 18421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yucong, Z. et al. Serum functional Dickkopf-1 levels are inversely correlated with radiographic severity of ankylosing spondylitis. Clin. Lab. 60, 1527–1531 (2014).

    Article  PubMed  Google Scholar 

  28. Ringold, S. et al. American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Care Res. (Hoboken) 71, 717–734 (2019).

    Article  PubMed  Google Scholar 

  29. Onel, K., Rumsey, D. G. & Shenoi, S. Juvenile idiopathic arthritis treatment updates. Rheum. Dis. Clin. North Am. 47, 545–563 (2021).

    Article  PubMed  Google Scholar 

  30. Fassio, A. et al. Inhibition of Tumor Necrosis Factor-Alpha (Tnf-Alpha) in patients with early rheumatoid arthritis results in acute changes of bone modulators. Int. Immunopharmacol. 67, 487–489 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Chen, T. L., Chang, K. H. & Su, K. Y. Effects of biological/targeted therapies on bone mineral density in inflammatory arthritis. Int. J. Mol. Sci. 23, 4111 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Adami, G. et al. Effects of Tnf inhibitors on parathyroid hormone and Wnt signaling antagonists in rheumatoid arthritis. Calcif. Tissue Int. 99, 360–364 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Świerkot, J., Gruszecka, K., Matuszewska, A. & Wiland, P. Assessment of the effect of methotrexate therapy on bone metabolism in patients with rheumatoid arthritis. Arch. Immunol. Ther. Exp. (Warsz.) 63, 397–404 (2015).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank all the children and their parents for their generous and enthusiastic assistance during the phase of data collection. Besides, the contribution of Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine in recording data is heartfeltly appreciated.

Funding

Shanghai Municipal Health Planning Committee Project (201740233).

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Authors and Affiliations

Authors

Contributions

L.Y. carried out the ELISA experiment, analyzed the data, and drafted the manuscript. J.W. designed and participated in experiments. H.H., F.D., X.X., C.L., and S.B. helped with coordination. Y.J. and J.W. conceived the study, designed and participated in experiments, and revised the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Jing Wu or Yanliang Jin.

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The authors declare no competing interests.

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The studies involving human participants were reviewed and approved by the Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine.

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Ye, L., Jin, Y., Huang, H. et al. The plasma levels of Dickkopf-1 elevated in patients with Juvenile Idiopathic Arthritis. Pediatr Res 94, 1349–1354 (2023). https://doi.org/10.1038/s41390-023-02637-8

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  • DOI: https://doi.org/10.1038/s41390-023-02637-8

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