Skip to main content

Advertisement

SpringerLink
Log in

Evaluating the role of serum sclerostin as an indicator of activity and damage in Egyptian patients with rheumatoid arthritis: university hospital experience

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objective

Sclerostin is an osteocyte-derived glycoprotein which inhibits the canonical Wnt pathway essential for osteoblastic activity decreasing bone formation. Its potential role in rheumatoid arthritis (RA) pathogenesis was highlighted by experimental studies. Here we measured the serum sclerostin in RA patients and evaluated its relationship with disease activity and damage.

Methods

One hundred RA patients and 80 age and sex-matched healthy controls were enrolled in the study. Bone biomarkers were evaluated for all participants including total calcium, phosphorus, alkaline phosphatase, 25-hydroxy vitamin D, and intact parathyroid hormone, in addition to fibroblast growth factor-23 (FGF23) and serum sclerostin. For RA patients, carotid intima-media thickness, brachial artery flow dilatation, and musculoskeletal ultrasonography using ultrasonography-7 joint score were done, and DAS28-ESR was calculated.

Results

Median serum sclerostin in our patients was 186.5 ± 22.7 pg/ml which was significantly higher than in controls 60.6 ± 7.1 pg/ml (p < 0.002). Serum sclerostin showed no correlation with disease activity, bone erosions, carotid intima-media thickness, brachial flow dilatation, and the examined bone biomarkers. However, it had a strong correlation with FGF23 (r coefficient 0.988, p < 0.000).

Conclusion

Although serum sclerostin was elevated in RA patients, it could not be used as a prognostic marker for disease activity, bone erosions or atherosclerosis.

Key Points

• Serum sclerostin may not reflect changes in the joint microenvironment being not correlated with ultrasonography-detected synovitis or erosions.

• Serum sclerostin was elevated in RA patients irrespective to their age or gender.

• The positive correlation with FGF23 may provide evidence for sclerostin contribution in bone demineralization in RA patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Article Open access 01 July 2023

Enisa Shevroja, Jean-Yves Reginster, … Nicholas C. Harvey

References

  1. Firestein GS, McInnes IB (2017) Immunopathogenesis of rheumatoid arthritis. Immunity 46(2):183–196. https://doi.org/10.1016/j.immuni.2017.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Goldring SR (2015) Inflammatory signaling induced bone loss. Bone 80:143–149. https://doi.org/10.1016/j.bone.2015.05.024

    Article  CAS  PubMed  Google Scholar 

  3. Corrado A, Maruotti N, Cantatore FP (2017) Osteoblast role in rheumatic diseases. Int J Mol Sci 18(6):1272. https://doi.org/10.3390/ijms18061272

    Article  CAS  PubMed Central  Google Scholar 

  4. Bosello S, Fedele AL, Peluso G, Gremese E, Tolusso B, Ferraccioli G (2011) Very early rheumatoid arthritis is the major predictor of major outcomes: clinical ACR remission and radiographic non-progression. Ann Rheum Dis 70(7):1292–1295. https://doi.org/10.1136/ard.2010.142729

    Article  PubMed  Google Scholar 

  5. Rossini M, Fassio A, Idolazzi L, Viapiana O, Fracassi E, Adami G et al (2015) Pathogenesis of bone erosions in rheumatoid arthritis: not only inflammation. J Rheum Dis Treat 1(2):1–5

    Article  Google Scholar 

  6. Baum R, Gravallese EM (2016) Bone as a target organ in rheumatic disease: impact on osteoclasts and osteoblasts. Clin Rev Allergy Immunol 51(1):1–15. https://doi.org/10.1007/s12016-015-8515-6.Bone

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wazen RM, Kuroda S, Nishio C, Sellin K, Brunski JB, Nanci A (2014) Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum 8(9):1385–1395. https://doi.org/10.2217/nnm.12.167.Gene

    Article  Google Scholar 

  8. Rabelo FDS, da Mota LMH, Lima RAC, Lima FAC, Barra GB, de Carvalho JF, Amato AA (2010) The Wnt signaling pathway and rheumatoid arthritis. Autoimmun Rev 9(4):207–210. https://doi.org/10.1016/j.autrev.2009.08.003

    Article  CAS  Google Scholar 

  9. Delgado-Calle J, Sato AY, Bellido T (2017) Role and mechanism of action of sclerostin in bone. Bone 96:29–37. https://doi.org/10.1016/j.bone.2016.10.007

    Article  CAS  PubMed  Google Scholar 

  10. Daoussis D, Andonopoulos AP, Liossis SNC (2010) Wnt pathway and IL-17: novel regulators of joint remodeling in rheumatic diseases. Looking beyond the RANK-RANKL-OPG Axis. Semin Arthritis Rheum 39(5):369–383. https://doi.org/10.1016/j.semarthrit.2008.10.008

    Article  CAS  PubMed  Google Scholar 

  11. Miao CG, Yang YY, He X, Li XF, Huang C, Huang Y et al (2013) Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal 25(10):2069–2078. https://doi.org/10.1016/j.cellsig.2013.04.002

    Article  CAS  PubMed  Google Scholar 

  12. Brandenburg VM, D’Haese P, Deck A, Mekahli D, Meijers B, Neven E, Evenepoel P (2016) From skeletal to cardiovascular disease in 12 steps—the evolution of sclerostin as a major player in CKD-MBD. Pediatr Nephrol 31(2):195–206. https://doi.org/10.1007/s00467-015-3069-7

    Article  PubMed  Google Scholar 

  13. Pietrzyk B, Smertka M, Chudek J (2017) Sclerostin: intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders. Adv Clin Exp Med 26(8):1283–1291. https://doi.org/10.17219/acem/68739

    Article  PubMed  Google Scholar 

  14. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM, Atkins GJ (2011) Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One 6(10). https://doi.org/10.1371/journal.pone.0025900

  15. Suen PK, Qin L (2016) Sclerostin, an emerging therapeutic target for treating osteoporosis and osteoporotic fracture: a general review. J Orthopaed Transl 4:1–13. https://doi.org/10.1016/j.jot.2015.08.004

    Article  Google Scholar 

  16. Ma Y, Zhang X, Wang M, Xia Q, Yang J, Wu M et al (2018) The serum level of Dickkopf-1 in patients with rheumatoid arthritis: a systematic review and meta-analysis. Int Immunopharmacol 59(April):227–232. https://doi.org/10.1016/j.intimp.2018.04.019

    Article  CAS  PubMed  Google Scholar 

  17. Sma A, Mg Z (2015) Role of Dickkopf-1 and musculoskeletal ultrasound in bone loss in rheumatoid arthritis. J Med Diagnos Methods 04(04). https://doi.org/10.4172/2168-9784.1000185

  18. Gómez-Vaquero C, Martín I, Loza E, Carmona L, Ivorra J, Narváez JA et al (2016) Effect of osteoprotegerin and dickkopf-related protein 1 on radiological progression in tightly controlled rheumatoid arthritis. PLoS One 11(12):1–11. https://doi.org/10.1371/journal.pone.0166691

    Article  CAS  Google Scholar 

  19. Paccou J, Mentaverri R, Renard C, Liabeuf S, Fardellone P, Massy Z a et al (2014) The relationships between serum sclerostin, bone mineral density, and vascular calcification in rheumatoid arthritis. J Clin Endocrinol Metab 99(12):4740–4748. https://doi.org/10.1210/jc.2014-2327

    Article  CAS  PubMed  Google Scholar 

  20. El-Bakry S, Saber N, Zidan H, Samaha D (2016) Sclerostin as an innovative insight towards understanding rheumatoid arthritis. Egyptian Rheumatol 38(2):71–75. https://doi.org/10.1016/j.ejr.2015.05.001

    Article  Google Scholar 

  21. Mehaney D, M, E., S, A, Fakhr El-din S (2015) Serum sclerostin level among Egyptian rheumatoid arthritis patients: relation to disease activity , bone mineral density and radiological grading. Acta Reumatol Port 40:268–274

    CAS  PubMed  Google Scholar 

  22. Seror R, Boudaoud S, Pavy S, Nocturne G, Schaeverbeke T, Saraux A et al (2016) Increased Dickkopf-1 in recent-onset rheumatoid arthritis is a new biomarker of structural severity. Data from the ESPOIR cohort. Sci Rep 6:1–11. https://doi.org/10.1038/srep18421

    Article  CAS  Google Scholar 

  23. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581. https://doi.org/10.1002/art.27584

    Article  PubMed  Google Scholar 

  24. Smolen JS, Aletaha D (2008) Activity assessments in rheumatoid arthritis. Curr Opin Rheumatol 20(3):306–313. https://doi.org/10.1097/BOR.0b013e3282fbd382

    Article  PubMed  Google Scholar 

  25. Wolfe F, Pincus T (1999) Listening to the patient: a practical guide to self-report questionnaires in clinical care. Arthritis Rheum 42(9):1797–1808. https://doi.org/10.1002/1529-0131(199909)42:9<1797::AID-ANR2>3.0.CO;2-Q

    Article  CAS  PubMed  Google Scholar 

  26. Backhaus M, Ohrndorf S, Kellner H, Strunk J, Backhaus TM, Hartung W et al (2009) Evaluation of a novel 7-joint ultrasound score in daily rheumatologic practice: a pilot project. Arthritis Care Res 61(9):1194–1201. https://doi.org/10.1002/art.24646

    Article  CAS  Google Scholar 

  27. Naredo E, Wakefield RJ, Iagnocco A, Terslev L, Filippucci E, Gandjbakhch F et al (2011) The OMERACT ultrasound task force - status and perspectives. J Rheumatol 38(9):2063–2067. https://doi.org/10.3899/jrheum.110425

    Article  PubMed  Google Scholar 

  28. Wikstrand JCM (2012) Methodological considerations of ultrasound measurement of carotid artery intima-media thickness and lumen diameter. Ultrasound Carotid Bifurcation Atherosclerosis 9781848826:165–176. https://doi.org/10.1007/978-1-84882-688-5_10

    Article  Google Scholar 

  29. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M et al (2013) 2013 ESH/ESC guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 34(28):2159–2219. https://doi.org/10.1093/eurheartj/eht151

    Article  PubMed  Google Scholar 

  30. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager M a et al (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force. J Am Coll Cardiol 39(2):257–265. https://doi.org/10.1016/S0735-1097(01)01746-6

    Article  PubMed  Google Scholar 

  31. Rodriguez-Miguelez P, Seigler N, Harris R a (2016) Ultrasound assessment of endothelial function: a technical guideline of the flow-mediated dilation test. J Vis Exp 2016(110):1–10. https://doi.org/10.3791/54011

    Article  CAS  Google Scholar 

  32. Luo C, Li Y, Liu D, Hu C, Du Z (2012) The association of brachial flow-mediated dilation and high-sensitivity C-reactive protein levels with Duke treadmill score in patients with suspected microvascular angina. Exp Clin Cardiol 17(4):197–201

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Drake MT, Khosla S (2017) Hormonal and systemic regulation of sclerostin. Bone 96:8–17. https://doi.org/10.1016/j.bone.2016.12.004

    Article  CAS  PubMed  Google Scholar 

  34. Chen XX, Baum W, Dwyer D, Stock M, Schwabe K, Ke HZ et al (2013) Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis. Ann Rheum Dis 72(10):1732–1736. https://doi.org/10.1136/annrheumdis-2013-203345

    Article  CAS  PubMed  Google Scholar 

  35. Courbon G, Lamarque R, Gerbaix M, Caire R, Linossier MT, Laroche N et al (2018) Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model. Sci Rep 8(1):2–11. https://doi.org/10.1038/s41598-018-21886-w

    Article  CAS  Google Scholar 

  36. Vincent C, Findlay DM, Welldon KJ, Wijenayaka AR, Zheng TS, Haynes DR et al (2009) Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFα induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts. J Bone Miner Res 24(8):1434–1449. https://doi.org/10.1359/jbmr.090305

    Article  CAS  PubMed  Google Scholar 

  37. Lee YH, Bae SC (2016) Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: a meta-analysis. Clin Exp Rheumatol 34(5):827–833

    PubMed  Google Scholar 

  38. Walwadkar SD, Suryakar AN, Katkam RV, Kumbar KM, Ankush RD (2006) Oxidative stress and calcium-phosphorus levels in rheumatoid arthritis. Indian J Clin Biochem 21(2):134–137. https://doi.org/10.1007/BF02912928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mahmoud A, Ismail M (2012) Anemia, iron status and calcium-phosphorus levels in rheumatoid arthritis patients. Nat Sci 10(7):110–114

  40. Jaskiewicz F (2000) Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 318(9):14. https://doi.org/10.1016/j.yexcr.2012.02.027.Role

    Article  Google Scholar 

  41. Sato H, James Kazama J, Murasawa A, Otani H, Abe A, Ito S et al (2016) Serum fibroblast growth factor 23 (FGF23) in patients with rheumatoid arthritis. Intern Med 55(2):121–126. https://doi.org/10.2169/internalmedicine.55.5507

    Article  CAS  PubMed  Google Scholar 

  42. Atkins G, Rowe P, Lim H, Welldon K, Ormsby R (2012) Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Miner Res 26(7):1425–1436. https://doi.org/10.1002/jbmr.345.Sclerostin

    Article  Google Scholar 

  43. Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine M a, Kumar R, Schiavi SC (2001) FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun 284(4):977–981. https://doi.org/10.1006/bbrc.2001.5084

    Article  CAS  PubMed  Google Scholar 

  44. Ryan ZC, Ketha H, McNulty MS, McGee-Lawrence M, Craig T a, Grande JP et al (2013) Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium. Proc Natl Acad Sci 110(15):6199–6204. https://doi.org/10.1073/pnas.1221255110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Im CH, Kim NR, Kang JW, Kim JH, Kang JY, Bae GB et al (2014) Inflammatory burden interacts with conventional cardiovascular risk factors for carotid plaque formation in rheumatoid arthritis. Rheumatology (United Kingdom) 54(5):808–815. https://doi.org/10.1093/rheumatology/keu376

    Article  CAS  Google Scholar 

  46. Marinou K, Christodoulides C, Antoniades C, Koutsilieris M (2012) Wnt signaling in cardiovascular physiology. Trends Endocrinol Metab 23(12):628–636. https://doi.org/10.1016/j.tem.2012.06.001

    Article  CAS  PubMed  Google Scholar 

  47. Novo-Rodríguez C, García-Fontana B, De Dios Luna-Del Castillo J, Andújar-Vera F, Avila-Rubio V, García-Fontana C et al (2018) Circulating levels of sclerostin are associated with cardiovascular mortality. PLoS One 13(6):1–14. https://doi.org/10.1371/journal.pone.0199504

    Article  CAS  Google Scholar 

  48. Brandenburg VM, Kramann R, Koos R, Krüger T, Schurgers L, Mühlenbruch G et al (2013) Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study. BMC Nephrol 14(1). https://doi.org/10.1186/1471-2369-14-219

  49. Szkudlarek M, Narvestad E, Klarlund M, Court-Payen M, Thomsen HS, Østergaard M (2004) Ultrasonography of the metatarsophalangeal joints in rheumatoid arthritis: comparison with magnetic resonance imaging, conventional radiography, and clinical examination. Arthritis Rheum 50(7):2103–2112. https://doi.org/10.1002/art.20333

    Article  PubMed  Google Scholar 

  50. El-Gohary RM, Ahmed Mahmoud AAM, Khalil A, El-Gendy H, Gado KH (2019) Validity of 7-joint versus simplified 12-joint ultrasonography scoring systems in assessment of rheumatoid arthritis activity. J Clin Rheumatol 25(6):264–271. https://doi.org/10.1097/RHU.0000000000000847

    Article  PubMed  Google Scholar 

  51. Naredo E, Rodríguez M, Campos C, Rodríguez-Heredia JM, Medina J a, Giner E et al (2008) Validity, reproducibility, and responsiveness of a twelve-joint simplified power Doppler ultrasonographic assessment of joint inflammation in rheumatoid arthritis. Arthritis Care Res 59(4):515–522. https://doi.org/10.1002/art.23529

    Article  Google Scholar 

  52. Verheul MK, Fearon U, Trouw L a, Veale DJ (2015) Biomarkers for rheumatoid and psoriatic arthritis. Clin Immunol 161(1):2–10. https://doi.org/10.1016/j.clim.2015.04.005

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Nephrology Unit, Internal Medicine Department, Kasr Al-Ainy School of Medicine, Cairo University, Cairo, Egypt

    Ahmed Fayed

  2. Rheumatology & Clinical Immunology Unit, Internal Medicine Department, Kasr Al-Ainy School of Medicine, Cairo University, Al-Saray St., El-Maniel, Cairo, 11562, Egypt

    Rasmia Elgohary & Mary Fawzy

Authors
  1. Ahmed Fayed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rasmia Elgohary
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary Fawzy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors have contributed significantly and equally in the design of this work, data acquisition, analysis, and interpretation. In addition to the writing and revising of this manuscript, all authors approved the final version before submission.

Corresponding author

Correspondence to Rasmia Elgohary.

Ethics declarations

Disclosures

None.

Human rights

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical committee approval

The ethical committee of the Internal Medicine Department, Kasr Al-Ainy School of Medicine, Cairo University approved this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fayed, A., Elgohary, R. & Fawzy, M. Evaluating the role of serum sclerostin as an indicator of activity and damage in Egyptian patients with rheumatoid arthritis: university hospital experience. Clin Rheumatol 39, 1121–1130 (2020). https://doi.org/10.1007/s10067-019-04878-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-019-04878-7

Keywords

Search

Navigation