Clinical Rheumatology

, Volume 37, Issue 11, pp 3057–3062 | Cite as

Dickkopf-1 (Dkk-1) serum levels in systemic sclerosis and rheumatoid arthritis patients: correlation with the Trabecular Bone Score (TBS)

  • Barbara RuaroEmail author
  • Andrea Casabella
  • Sabrina Paolino
  • Carmen Pizzorni
  • Massimo Ghio
  • Chiara Seriolo
  • Luigi Molfetta
  • Patrizio Odetti
  • Vanessa Smith
  • Maurizio Cutolo
Original Article


The aim of this research was to determine any correlations between Dickkopf-1 serum levels (Dkk-1, a natural inhibitor of the Wnt signaling pathway promoting osteoclastogenesis) and the Trabecular Bone Score (TBS), in systemic sclerosis (SSc) and rheumatoid arthritis (RA) patients. It also aimed at determining any difference in Dkk-1 serum levels between SSc and RA patients and a control group (CNT) of healthy subjects. A prospective study was carried out in 60 SSc and 60 RA patients and 60 CNT. Dkk-1 serum levels were evaluated by the ELISA method (Quantikine Human Dkk-1 Immunoassay, R&D System, Minneapolis, USA). The severity of microvascular damage was evaluated by nailfold videocapillaroscopy (NVC patterns: “Early,” “Active,” “Late”), in the SSc patients. TBS analysis and bone mineral density (BMD, g/cm2) were measured in all patients/subjects. The SSc patients showed higher Dkk-1 serum levels than RA (p < 0.004) and CNT (p < 0.0001) patients. SSc patients, showing the “Late” NVC pattern had statistically higher Dkk-1 serum levels than patients with either the “Active” or “Early” (p < 0.004) patterns. Only in the “Late” NVC pattern group of SSc patients was there a significant negative correlation between Dkk-1 and TBS values (p < 0.0001). The increased Dkk-1 serum levels and decreased TBS values observed suggest a diffuse bone damage in SSc patients with advanced disease, as demonstrated by the concomitant presence of the “Late” NVC pattern. Moreover, the bone remodeling in SSc seems even higher than that in RA patients.


Dickkopf-1 Osteoporosis Rheumatoid arthritis Systemic sclerosis Trabecular Bone Score 



The authors would like to thank Barbara Wade, contract Professor at the University of Torino, for her linguistic advice.

Funding statement

No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this manuscript. Barbara Ruaro is supported by a Grant from the Italian Society of Rheumatology. Vanessa Smith is a Senior Clinical Investigator of the Research Foundation - Flanders (Belgium) (FWO) [1802915N].

Compliance with ethical standards



Ethical standards

This prospective study was carried out in accordance with the ethical standards stipulated in the 1964 Declaration of Helsinki and its later amendments and was evaluated by the local IRB.


  1. 1.
    Krishnan V, Bryant HU, Macdougald OA (2006) Regulation of bone mass by Wnt signaling. J Clin Invest 116:1202–1209CrossRefGoogle Scholar
  2. 2.
    Westendorf JJ, Kahler RA, Schroeder TM (2004) Wnt signaling in osteoblasts and bone diseases. Gene 341:19–39CrossRefGoogle Scholar
  3. 3.
    Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen J, Hoffmann M, Scheinecker C, van der Heide D, Landewe R, Lacey D, Richards WG, Schett G (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163CrossRefGoogle Scholar
  4. 4.
    Daoussis D, Andonopoulos AP (2011) The emerging role of Dickkopf-1 in bone biology: is it the main switch controlling bone and joint remodeling? Semin Arthritis Rheum 41:170–177CrossRefGoogle Scholar
  5. 5.
    Seror R, Boudaoud S, Pavy S, Nocturne G, Schaeverbeke T, Saraux A, Chanson P, Gottenberg JE, Devauchelle-Pensec V, Tobón GJ, Mariette X, Miceli-Richard C (2016) Increased Dickkopf-1 in recent-onset rheumatoid arthritis is a new biomarker of structural severity. Data from the ESPOIR cohort. Sci Rep 6:18421CrossRefGoogle Scholar
  6. 6.
    Cutolo M, Pizzorni C, Sulli A (2011) Vitamin D endocrine system involvement in autoimmune rheumatic diseases. Autoimmun Rev. 11:84–87CrossRefGoogle Scholar
  7. 7.
    Kim HR, Kim HY, Lee SH (2006) Elevated serum levels of soluble receptor activator of nuclear factors-kappaB ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS). Rheumatology 45:1197–1200CrossRefGoogle Scholar
  8. 8.
    Zhang L, Ouyang H, Xie Z, Liang ZH, Wu XW (2016) Serum DKK-1 level in the development of ankylosing spondylitis and rheumatic arthritis: a meta-analysis. Exp Mol Med 48:e228CrossRefGoogle Scholar
  9. 9.
    Yubo M, Xu Z, Mengmeng W et al (2018) The serum level of Dickkopf-1 in patients with rheumatoid arthritis: a systematic review and meta-analysis. Int Immunopharmacol 59:227–232CrossRefGoogle Scholar
  10. 10.
    Wu M, Chen M, Ma Y, Yang J, Han R, Yuan Y, Hu X, Wang M, Zhang X, Xu S, Liu R, Jiang G, Xu J, Shuai Z, Zou Y, Pan G, Pan F (2018) Dickkopf-1 in ankylosing spondylitis: review and meta-analysis. Clin Chim Acta 481:177–183CrossRefGoogle Scholar
  11. 11.
    Klavdianou K, Liossis SN, Sakkas L, Daoussis D (2017) The role of Dickkopf-1 in joint remodeling and fibrosis: a link connecting spondyloarthropathies and scleroderma? Semin Arthritis Rheum 46:430–438CrossRefGoogle Scholar
  12. 12.
    Daoussis D, Tsamandas A, Antonopoulos I, Filippopoulou A, Papachristou DJ, Papachristou NI, Andonopoulos AP, Liossis SN (2016) B cell depletion therapy up-regulates Dkk-1 skin expression in patients with systemic sclerosis: association with enhanced resolution of skin fibrosis. Arthritis Res Ther 18:118CrossRefGoogle Scholar
  13. 13.
    Dees C, Schlottmann I, Funke R, Distler A, Palumbo-Zerr K, Zerr P, Lin NY, Beyer C, Distler O, Schett G, Distler JHW (2014) The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis 73:1232–1239CrossRefGoogle Scholar
  14. 14.
    Lafyatis R (2012) Connective tissue disease: SSc-fibrosis takes flight with Wingless inhibition. Nat Rev Rheumatol 8:441–442CrossRefGoogle Scholar
  15. 15.
    Ruaro B, Casabella A, Paolino S, Pizzorni C, Alessandri E, Seriolo C, Botticella G, Molfetta L, Odetti P, Smith V, Cutolo M (2018) Correlation between bone quality and microvascular damage in systemic sclerosis patients. Rheumatology (Oxford) 2018;57:1548–1554CrossRefGoogle Scholar
  16. 16.
    Cutolo M, Pizzorni C, Tuccio M, Burroni A, Craviotto C, Basso M, Seriolo B, Sulli A (2004) Nailfold videocapillaroscopic patterns and serum autoantibodies in systemic sclerosis. Rheumatology 43:719–726CrossRefGoogle Scholar
  17. 17.
    Sulli A, Secchi ME, Pizzorni C, Cutolo M (2008) Scoring the nailfold microvascular changes during the capillaroscopic analysis in systemic sclerosis patients. Ann Rheum Dis 67:885–887CrossRefGoogle Scholar
  18. 18.
    Cutolo M, Ruaro B, Smith V (2017) Macrocirculation versus microcirculation and digital ulcers in systemic sclerosis patients. Rheumatology 56:1834–1836CrossRefGoogle Scholar
  19. 19.
    LeRoy EC, Meedsger TA Jr (2001) Criteria for the classification of early systemic sclerosis. J Rheumatol 28:1573–1576Google Scholar
  20. 20.
    Van den Hoogen F, Khanna D et al (2013) Classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 72:1747–1755Google Scholar
  21. 21.
    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League against Rheumatism Collaborative Initiative. Ann Rheum Dis 69:1580–1588CrossRefGoogle Scholar
  22. 22.
    Parfitt AM, Mathews CH, Villanueva AR, Kleerekoper M, Frame B, Rao DS (1983) Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest 72:1396–1409CrossRefGoogle Scholar
  23. 23.
    Hans D, Goertzen AL, Krieg MA, Leslie WD (2011) Bone microarchitecture assessed by TBS predicts osteoporotic fractures indipendent of bone density: the Manitoba study. J Bone Miner Res 26:2762–2769CrossRefGoogle Scholar
  24. 24.
    Harvey NC, Glüer CC, Binkley N, McCloskey EV, Brandi ML, Cooper C, Kendler D, Lamy O, Laslop A, Camargos BM, Reginster JY, Rizzoli R, Kanis JA (2015) Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation in clinical practice. Bone 78:216–224CrossRefGoogle Scholar
  25. 25.
    Lewiecki EM (2005) Review of guidelines for bone mineral density testing and treatment of osteoporosis. Curr Osteoporos Rep 3:75–83CrossRefGoogle Scholar
  26. 26.
    Chun KJ (2011) Bone densitometry. Semin Nucl Med 41:220–228CrossRefGoogle Scholar
  27. 27.
    El Maghraoui A, Roux C (2008) DXA scanning in clinical practice. QJM 101:605–617CrossRefGoogle Scholar
  28. 28.
    Cutolo M, Smith V (2013) State of the art on nailfold capillaroscopy: a reliable diagnostic tool and putative biomarker in rheumatology? Rheumatology 52:1933–1940CrossRefGoogle Scholar
  29. 29.
    Pizzorni C, Sulli A, Smith V, Ruaro B, Trombetta AC, Cutolo M, Paolino S (2017) Primary Raynaud’s phenomenon and nailfold videocapillaroscopy: age-related changes in capillary morphology. Clin Rheumatol 36:1637–1642CrossRefGoogle Scholar
  30. 30.
    Smith V, Beeckman S, Herrick AL, Decuman S, Deschepper E, de Keyser F, Distler O, Foeldvari I, Ingegnoli F, Müller-Ladner U, Riccieri V, Riemekasten G, Sulli A, Voskuyl A, Cutolo M, on behalf of the EULAR study group on microcirculation (2016) An EULAR study group pilot study on reliability of simple capillaroscopic definitions to describe capillary morphology in rheumatic diseases. Rheumatology 55:883–890CrossRefGoogle Scholar
  31. 31.
    Diarra D, Stolina M, Polzer K et al (2007) Dickkopf- 1 is a master regulator of joint remodeling. Nat Med 13:156–163CrossRefGoogle Scholar
  32. 32.
    Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, Schneider H, Sadowski A, Riener MO, MacDougald OA, Distler O, Schett G, Distler JHW (2012) Activation of canonical Wnt signaling is required for TGF-β-mediated fibrosis. Nat Commun 3:735CrossRefGoogle Scholar
  33. 33.
    Garnero P, Tabassi NC, Voorzanger-Rousselot N (2008) Circulating dickkopf-1 and radiological progression in patients with early rheumatoid arthritis treated with etanercept. J Rheumatol 35:2313–2315CrossRefGoogle Scholar
  34. 34.
    Shibuya K, Hagino H, Morio Y, Teshima R (2002) Cross-sectional and longitudinal study of osteoporosis in patients with rheumatoid arthritis. Clin Rheumatol 21:150–158CrossRefGoogle Scholar
  35. 35.
    Seriolo B, Paolino S, Casabella A, Botticella G, Seriolo C, Molfetta L (2013) Osteoporosis in the elderly. Aging Clin Exp Res 25:27–29CrossRefGoogle Scholar
  36. 36.
    Boyanov M, Robeva R, Popivanov P (2003) Bone mineral density changes in women with systemic lupus erythematosus. Clin Rheumatol 22:318–323CrossRefGoogle Scholar
  37. 37.
    Yilmaz N, Ozaslan J (2000) Biochemical bone turnover markers in patients with ankylosing spondylitis. Clin Rheumatol 19:92–98CrossRefGoogle Scholar
  38. 38.
    Cutolo M, Paolino S, Sulli A, Smith V, Pizzorni C, Seriolo B (2014) Vitamin D, steroid hormones, and autoimmunity. Ann N Y Acad Sci 1317:39–46CrossRefGoogle Scholar
  39. 39.
    Trombetta AC, Smith V, Gotelli E, Ghio M, Paolino S, Pizzorni C, Vanhaecke A, Ruaro B, Sulli A, Cutolo M (2017) Vitamin D deficiency and clinical correlations in systemic sclerosis patients: a retrospective analysis for possible future developments. PLoS One 12:e0179062CrossRefGoogle Scholar
  40. 40.
    Seriolo B, Molfetta L, Cutolo M (2011) Seasonal variations in serum levels of 25-hydroxyvitamin D in patients with systemic sclerosis. Clin Rheumatol 30:445–446CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  • Barbara Ruaro
    • 1
    Email author
  • Andrea Casabella
    • 1
    • 2
  • Sabrina Paolino
    • 1
  • Carmen Pizzorni
    • 1
  • Massimo Ghio
    • 1
  • Chiara Seriolo
    • 2
  • Luigi Molfetta
    • 2
  • Patrizio Odetti
    • 2
  • Vanessa Smith
    • 3
    • 4
  • Maurizio Cutolo
    • 1
  1. 1.Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine (Di.M.I.), Polyclinic San Martino HospitalUniversity of GenovaGenoaItaly
  2. 2.Centro di Ricerca su Osteoporosi e Patologie Osteoarticolari CROPO, Di.M.I.University of GenovaGenoaItaly
  3. 3.Department of RheumatologyGhent University HospitalGhentBelgium
  4. 4.Department of Internal MedicineGhent UniversityGhentBelgium

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