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Clinical Rheumatology

, Volume 37, Issue 11, pp 3093–3098 | Cite as

Parathyroid hormone is a determinant of serum Dickkopf-1 levels in ankylosing spondylitis

  • Giovanni OrsoliniEmail author
  • Giovanni Adami
  • Maurizio Rossini
  • Francesco Ghellere
  • Cristian Caimmi
  • Angelo Fassio
  • Luca Idolazzi
  • Davide Gatti
  • Ombretta Viapiana
Original Article
  • 121 Downloads

Abstract

Available studies reported contradictory results about serum levels Dickkopf-1 (DKK1), an inhibitor of Wnt signaling in patients with ankylosing spondylitis (AS). In previous studies, we observed in other conditions that parathyroid hormone (PTH) serum levels were an important determinant of DKK1 serum levels. The aim of the present study was to investigate it in patients with AS. We recruited 71 patients diagnosed with AS. Levels of C-reactive protein (CRP), DKK1, PTH, 25OH-vitamin D, and bone turnover markers (intact N-propeptide of type I collagen, P1NP, and C-terminal telopeptide of type I collagen, CTX) were measured and compared to healthy controls (HC). Dual X-ray absorptiometry at lumbar spine and proximal femoral site was used for bone mineral density (BMD) assessment and spine X-rays were also performed. PTH serum levels were found to be significantly higher in AS patients than in HC (33.8 ± 14.11 vs 24.8 ± 13 pg/ml, p = 0.002), while mean DKK1 serum levels were lower than in HC (23.3 ± 13.1 vs 29.8 ± 15.9 pmol/l, p = 0.009). A positive correlation between DKK1 and PTH (correlation coefficient + 0.25, p = 0.03) was observed; it remained significant in a multivariate analysis. In patients with longer disease duration, DKK1 was also positively correlated with CTX (coefficient 0.42, p = 0.01), and PTH was higher in those patients with low BMD (Z-score ≤ − 1) at any site (p = 0.04). Also in AS, PTH is an important determinant of DKK1 serum levels and should be evaluated in studies on DKK1. PTH might have a role in bone involvement in AS, also through the Wnt pathway.

Keywords

Ankylosing spondylitis Dickkopf-1 Osteoporosis Parathyroid hormone Wnt 

Notes

Compliance with ethical standards

The study protocol was in line with the Declaration of Helsinki. The study obtained a positive opinion and approval from the Ethical Committee of our institution.

Disclosures

None.

References

  1. 1.
    Khan MA, van der Linden SM (1990) Ankylosing spondylitis and other spondyloarthropathies. Rheum Dis Clin N Am 16(3):551–579Google Scholar
  2. 2.
    Braun J, Baraliakos X (2011) Imaging of axial spondyloarthritis including ankylosing spondylitis. Ann Rheum Dis 70(Suppl 1):i97–103. doi: https://doi.org/10.1136/ard.2010.140541 CrossRefGoogle Scholar
  3. 3.
    Carette S, Graham D, Little H, Rubenstein J, Rosen P (1983) The natural disease course of ankylosing spondylitis. Arthritis Rheum 26(2):186–190CrossRefGoogle Scholar
  4. 4.
    Marzo-Ortega H, Emery P, McGonagle D (2002) The concept of disease modification in spondyloarthropathy. J Rheumatol 29(8):1583–1585PubMedGoogle Scholar
  5. 5.
    Geusens P, Vosse D, van der Linden S (2007) Osteoporosis and vertebral fractures in ankylosing spondylitis. Curr Opin Rheumatol 19(4):335–339.  https://doi.org/10.1097/BOR.0b013e328133f5b3 CrossRefPubMedGoogle Scholar
  6. 6.
    Klingberg E, Lorentzon M, Gothlin J, Mellstrom D, Geijer M, Ohlsson C, Atkinson EJ, Khosla S, Carlsten H, Forsblad-d’Elia H (2013) Bone microarchitecture in ankylosing spondylitis and the association with bone mineral density, fractures, and syndesmophytes. Arthritis Res Ther 15(6):R179.  https://doi.org/10.1186/ar4368 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Robinson Y, Sanden B, Olerud C (2013) Increased occurrence of spinal fractures related to ankylosing spondylitis: a prospective 22-year cohort study in 17,764 patients from a national registry in Sweden. Patient Saf Surg 7(1):2.  https://doi.org/10.1186/1754-9493-7-2 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Munoz-Ortego J, Vestergaard P, Rubio JB, Wordsworth P, Judge A, Javaid MK, Arden NK, Cooper C, Diez-Perez A, Prieto-Alhambra D (2014) Ankylosing spondylitis is associated with an increased risk of vertebral and nonvertebral clinical fractures: a population-based cohort study. J Bone Miner Res 29(8):1770–1776.  https://doi.org/10.1002/jbmr.2217 CrossRefPubMedGoogle Scholar
  9. 9.
    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(2):156–163.  https://doi.org/10.1038/nm1538 CrossRefGoogle Scholar
  10. 10.
    Haynes KR, Pettit AR, Duan R, Tseng HW, Glant TT, Brown MA, Thomas GP (2012) Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Res Ther 14(6):R253.  https://doi.org/10.1186/ar4096 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K, Karampetsou M, Yiannopoulos G, Andonopoulos AP (2010) Evidence that DKK-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum 62(1):150–158.  https://doi.org/10.1002/art.27231 CrossRefPubMedGoogle Scholar
  12. 12.
    Liao HT, Lin YF, Tsai CY, Chou TC (2017) Bone morphogenetic proteins and Dickkopf-1 in ankylosing spondylitis. Scand J Rheumatol 47:1–6.  https://doi.org/10.1080/03009742.2017.1287305 CrossRefGoogle Scholar
  13. 13.
    Uderhardt S, Diarra D, Katzenbeisser J, David JP, Zwerina J, Richards W, Kronke G, Schett G (2010) Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis 69(3):592–597.  https://doi.org/10.1136/ard.2008.102046 CrossRefPubMedGoogle Scholar
  14. 14.
    Senolt L, Hulejova H, Krystufkova O, Forejtova S, Andres Cerezo L, Gatterova J, Pavelka K, Vencovsky J (2012) Low circulating Dickkopf-1 and its link with severity of spinal involvement in diffuse idiopathic skeletal hyperostosis. Ann Rheum Dis 71(1):71–74.  https://doi.org/10.1136/annrheumdis-2011-200357 CrossRefPubMedGoogle Scholar
  15. 15.
    MacDonald BT, Joiner DM, Oyserman SM, Sharma P, Goldstein SA, He X, Hauschka PV (2007) Bone mass is inversely proportional to DKK1 levels in mice. Bone 41(3):331–339.  https://doi.org/10.1016/j.bone.2007.05.009 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD, Jr. (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349 (26):2483–2494. doi: https://doi.org/10.1056/NEJMoa030847 CrossRefGoogle Scholar
  17. 17.
    Seror R, Boudaoud S, Pavy S, Nocturne G, Schaeverbeke T, Saraux A, Chanson P, Gottenberg JE, Devauchelle-Pensec V, Tobon 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 6:18421.  https://doi.org/10.1038/srep18421 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Nocturne G, Pavy S, Boudaoud S, Seror R, Goupille P, Chanson P, van der Heijde D, van Gaalen F, Berenbaum F, Mariette X, Briot K, Feydy A, Claudepierre P, Dieude P, Nithitham J, Taylor KE, Criswell LA, Dougados M, Roux C, Miceli-Richard C (2015) Increase in Dickkopf-1 serum level in recent spondyloarthritis. Data from the DESIR cohort. PLoS One 10(8):e0134974.  https://doi.org/10.1371/journal.pone.0134974 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sakellariou GT, Iliopoulos A, Konsta M, Kenanidis E, Potoupnis M, Tsiridis E, Gavana E, Sayegh FE (2017) Serum levels of DKK-1, sclerostin and VEGF in patients with ankylosing spondylitis and their association with smoking, and clinical, inflammatory and radiographic parameters. Joint Bone Spine 84(3):309–315.  https://doi.org/10.1016/j.jbspin.2016.05.008 CrossRefPubMedGoogle Scholar
  20. 20.
    Jadon DR, Sengupta R, Nightingale A, Lu H, Dunphy J, Green A, Elder JT, Nair RP, Korendowych E, Lindsay MA, McHugh NJ (2017) Serum bone-turnover biomarkers are associated with the occurrence of peripheral and axial arthritis in psoriatic disease: a prospective cross-sectional comparative study. Arthritis Res Ther 19(1):210.  https://doi.org/10.1186/s13075-017-1417-7 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, Colak A, Yalcin H, Gunay N, Akkoc N (2012) Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis. BMC Musculoskelet Disord 13:191.  https://doi.org/10.1186/1471-2474-13-191 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    de Andrade KR, de Castro GR, Vicente G, da Rosa JS, Nader M, Pereira IA, Frode TS (2014) Evaluation of circulating levels of inflammatory and bone formation markers in axial spondyloarthritis. Int Immunopharmacol 21(2):481–486.  https://doi.org/10.1016/j.intimp.2014.05.031 CrossRefPubMedGoogle Scholar
  23. 23.
    Yucong Z, Lu L, Shengfa L, Yongliang Y, Ruguo S, Yikai L (2014) Serum functional dickkopf-1 levels are inversely correlated with radiographic severity of ankylosing spondylitis. Clin Lab 60(9):1527–1531PubMedGoogle Scholar
  24. 24.
    Kwon SR, Lim MJ, Suh CH, Park SG, Hong YS, Yoon BY, Kim HA, Choi HJ, Park W (2012) 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(8):2523–2527.  https://doi.org/10.1007/s00296-011-1981-0 CrossRefPubMedGoogle Scholar
  25. 25.
    Rossini M, Viapiana O, Idolazzi L, Ghellere F, Fracassi E, Troplini S, Povino MR, Kunnathully V, Adami S, Gatti D (2016) Higher level of Dickkopf-1 is associated with low bone mineral density and higher prevalence of vertebral fractures in patients with ankylosing spondylitis. Calcif Tissue Int 98(5):438–445.  https://doi.org/10.1007/s00223-015-0093-3 CrossRefPubMedGoogle Scholar
  26. 26.
    Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H, Baraliakos X, Listing J, Rudwaleit M, Schett G, Sieper J (2012) High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 71(4):572–574.  https://doi.org/10.1136/annrheumdis-2011-200216 CrossRefPubMedGoogle Scholar
  27. 27.
    Rossini M, Viapiana O, Adami S, Fracassi E, Idolazzi L, Dartizio C, Povino MR, Orsolini G, Gatti D (2015) In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. Clin Exp Rheumatol 33(1):77–83PubMedGoogle Scholar
  28. 28.
    Viapiana O, Fracassi E, Troplini S, Idolazzi L, Rossini M, Adami S, Gatti D (2013) Sclerostin and DKK1 in primary hyperparathyroidism. Calcif Tissue Int 92(4):324–329.  https://doi.org/10.1007/s00223-012-9665-7 CrossRefPubMedGoogle Scholar
  29. 29.
    Rossini M, Viapiana O, Zanotti R, Tripi G, Perbellini O, Idolazzi L, Bonifacio M, Adami S, Gatti D (2015) Dickkopf-1 and sclerostin serum levels in patients with systemic mastocytosis. Calcif Tissue Int 96(5):410–416.  https://doi.org/10.1007/s00223-015-9969-5 CrossRefPubMedGoogle Scholar
  30. 30.
    Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S (2011) The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1. J Clin Endocrinol Metab 96(5):1555–1559.  https://doi.org/10.1210/jc.2010-2552 CrossRefPubMedGoogle Scholar
  31. 31.
    Cooper C, Carbone L, Michet CJ, Atkinson EJ, O'Fallon WM, Melton LJ 3rd (1994) Fracture risk in patients with ankylosing spondylitis: a population based study. J Rheumatol 21(10):1877–1882PubMedGoogle Scholar
  32. 32.
    Rossini M, Bagnato G, Frediani B, Iagnocco A, G LAM, Minisola G, Caminiti M, Varenna M, Adami S (2011) Relationship of focal erosions, bone mineral density, and parathyroid hormone in rheumatoid arthritis. J Rheumatol 38(6):997–1002.  https://doi.org/10.3899/jrheum.100829 CrossRefPubMedGoogle Scholar
  33. 33.
    Fraser WD (2009) Hyperparathyroidism. Lancet 374(9684):145–158.  https://doi.org/10.1016/S0140-6736(09)60507-9 CrossRefPubMedGoogle Scholar
  34. 34.
    Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, Chandrasekhar S, Martin TJ, Onyia JE (2001) Catabolic effects of continuous human PTH (1-38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology 142(9):4047–4054.  https://doi.org/10.1210/endo.142.9.8356 CrossRefPubMedGoogle Scholar
  35. 35.
    Fujita K, Janz S (2007) Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF. Mol Cancer 6:71.  https://doi.org/10.1186/1476-4598-6-71 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Boussoualim K, Amouzougan A, Pallot-Prades B, Denarie D, Collet P, Marotte H, Thomas T (2018) Evaluation of bone quality with trabecular bone score in active spondyloarthritis. Joint Bone Spine.  https://doi.org/10.1016/j.jbspin.2018.02.006
  37. 37.
    Karberg K, Zochling J, Sieper J, Felsenberg D, Braun J (2005) Bone loss is detected more frequently in patients with ankylosing spondylitis with syndesmophytes. J Rheumatol 32(7):1290–1298PubMedGoogle Scholar
  38. 38.
    Vosse D, Landewe R, van der Heijde D, van der Linden S, van Staa TP, Geusens P (2009) Ankylosing spondylitis and the risk of fracture: results from a large primary care-based nested case-control study. Ann Rheum Dis 68(12):1839–1842.  https://doi.org/10.1136/ard.2008.100503 CrossRefPubMedGoogle Scholar
  39. 39.
    Ghozlani I, Ghazi M, Nouijai A, Mounach A, Rezqi A, Achemlal L, Bezza A, El Maghraoui A (2009) Prevalence and risk factors of osteoporosis and vertebral fractures in patients with ankylosing spondylitis. Bone 44(5):772–776.  https://doi.org/10.1016/j.bone.2008.12.028 CrossRefPubMedGoogle Scholar
  40. 40.
    Klingberg E, Geijer M, Gothlin J, Mellstrom D, Lorentzon M, Hilme E, Hedberg M, Carlsten H, Forsblad-D'Elia H (2012) Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. J Rheumatol 39(10):1987–1995.  https://doi.org/10.3899/jrheum.120316 CrossRefPubMedGoogle Scholar
  41. 41.
    Klingberg E, Lorentzon M, Mellstrom D, Geijer M, Gothlin J, Hilme E, Hedberg M, Carlsten H, Forsblad-d'Elia H (2012) Osteoporosis in ankylosing spondylitis—prevalence, risk factors and methods of assessment. Arthritis Res Ther 14(3):R108.  https://doi.org/10.1186/ar3833 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Fassio A, Idolazzi L, Viapiana O, Benini C, Vantaggiato E, Bertoldo F, Rossini M, Gatti D (2017) In psoriatic arthritis DKK-1 and PTH are lower than in rheumatoid arthritis and healthy controls. Clin Rheumatol 36(10):2377–2381.  https://doi.org/10.1007/s10067-017-3734-2 CrossRefPubMedGoogle Scholar
  43. 43.
    Liu XH, Kirschenbaum A, Weinstein BM, Zaidi M, Yao S, Levine AC (2010) Prostaglandin E2 modulates components of the Wnt signaling system in bone and prostate cancer cells. Biochem Biophys Res Commun 394(3):715–720.  https://doi.org/10.1016/j.bbrc.2010.03.057 CrossRefPubMedGoogle Scholar
  44. 44.
    Kroon FP, van der Burg LR, Ramiro S, Landewe RB, Buchbinder R, Falzon L, van der Heijde D (2015) Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis). Cochrane Database Syst Rev 7:CD010952.  https://doi.org/10.1002/14651858.CD010952.pub2 CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  • Giovanni Orsolini
    • 1
    Email author
  • Giovanni Adami
    • 1
  • Maurizio Rossini
    • 1
  • Francesco Ghellere
    • 1
  • Cristian Caimmi
    • 1
  • Angelo Fassio
    • 1
  • Luca Idolazzi
    • 1
  • Davide Gatti
    • 1
  • Ombretta Viapiana
    • 1
  1. 1.University of Verona, Rheumatology UnitVeronaItaly

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