Skip to main content

Advertisement

SpringerLink
Log in

Interplay between low plasma RANKL and VDR-FokI polymorphism in lumbar disc herniation independently from age, body mass, and environmental factors: a case–control study in the Italian population

  • Original Article
  • Published:
European Spine Journal Aims and scope Submit manuscript

A Correction to this article was published on 07 February 2020

This article has been updated

Abstract

Purpose

Aim of this study was to investigate RANKL and osteoprotegerin plasma concentrations in patients affected by disc herniation, the most common epiphenomenon of disc degenerative diseases, and in a matched cohort of healthy subjects and whether the expression of these markers was associated to a polymorphism of the vitamin D receptor gene.

Methods

For this case–control study, 110 consecutive cases affected by lumbar disc herniation (confirmed by MRI) and 110 healthy age- and sex-matched controls were enrolled. Subjects affected by any other pathology were excluded. RANKL and osteoprotegerin were measured in plasma by immunoassays. The difference in these markers between cases and controls was assessed by t test. The correlation between osteoimmunological markers concentrations, anthropometrical variables, and the expression of the pathology was statistically assessed (Pearson’s test) along with the association (Fisher’s exact test) with the vitamin D receptor gene genotype, determined elsewhere.

Results

Despite comparable osteoprotegerin concentrations, cases, altogether or grouped for gender, express lower RANKL and, consequently, RANKL-to-osteoprotegerin ratio. While in cases RANKL and osteoprotegerin concentrations were independent from age and BMI, in controls they increased with age. Disc herniation was strongly associated with RANKL and the presence of the F allele of the VDR gene.

Conclusions

Whether vertebral bone changes precede or follow cartilage deterioration in intervertebral disc degeneration is not known. Our results suggest a reduced bone turnover rate, associated to a specific genetic background, in patients affected by lumbar disc herniation which could be one of the favoring factors for disc degeneration.

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
Fig. 2
Fig. 3

Similar content being viewed by others

Change history

  • 07 February 2020

    Under the headline ���Correlation of RANKL concentrations and VDR-FokI polymorphism on disc herniation��� in the description text for Table��2, the term ���allelic frequency��� was used erroneously for ���genotypic frequency���

References

  1. Noble BS, Peet N, Stevens HY, Brabbs A, Mosley JR, Reilly GC, Reeve J, Skerry TM, Lanyon LE (2003) Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. Am J Physiol Cell Physiol 284(4):C934–C943

    Article  PubMed  CAS  Google Scholar 

  2. Sims NA, Martin TJ (2014) Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BoneKey Rep 3:481

    PubMed  PubMed Central  Google Scholar 

  3. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390(6656):175–179

    Article  PubMed  CAS  Google Scholar 

  4. Kanematsu M, Sato T, Takai H, Watanabe K, Ikeda K, Yamada Y (2000) Prostaglandin E2 induces expression of receptor activator of nuclear factor-kappa B ligand/osteoprotegrin ligand on pre-B cells: implications for accelerated osteoclastogenesis in estrogen deficiency. J Bone Miner Res 15(7):1321–1329

    Article  PubMed  CAS  Google Scholar 

  5. Guerrini MM, Takayanagi H (2014) The immune system, bone and RANKL. Arch Biochem Biophys 561:118–123

    Article  PubMed  CAS  Google Scholar 

  6. Kanazawa K, Kudo A (2005) Self-assembled RANK induces osteoclastogenesis ligand-independently. J Bone Miner Res 20(11):2053–2060

    Article  PubMed  CAS  Google Scholar 

  7. Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, Gomibuchi T, Yano K, Shima N, Washida N, Tsuda E, Morinaga T, Higashio K, Ozawa H (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247(3):610–615

    Article  PubMed  CAS  Google Scholar 

  8. Colombini A, Lombardi G, Galliera E, Dogliotti G, Randelli P, Meerssemann A, Mineo G, Cabitza P, Corsi MM (2011) Plasma and drainage fluid levels of soluble receptor activator of nuclear factor-kB (sRANK), soluble receptor activator of nuclear factor-kB ligand (sRANKL) and osteoprotegerin (OPG) during proximal humerus fracture healing. Int Orthop 35(5):777–782

    Article  PubMed  PubMed Central  Google Scholar 

  9. Onal M, Xiong J, Chen X, Thostenson JD, Almeida M, Manolagas SC, O’Brien CA (2012) Receptor activator of nuclear factor kappaB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J Biol Chem 287(35):29851–29860

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N, Grabowski P, Del Fattore A, Messina C, Errigo G, Coxon FP, Scott DI, Teti A, Rogers MJ, Vezzoni P, Villa A, Helfrich MH (2007) Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 39(8):960–962

    Article  PubMed  CAS  Google Scholar 

  11. Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7(4):292–304

    Article  PubMed  CAS  Google Scholar 

  12. Hashizume M, Hayakawa N, Mihara M (2008) IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology 47(11):1635–1640

    Article  PubMed  CAS  Google Scholar 

  13. Jadon DR, Nightingale AL, McHugh NJ, Lindsay MA, Korendowych E, Sengupta R (2015) Serum soluble bone turnover biomarkers in psoriatic arthritis and psoriatic spondyloarthropathy. J Rheumatol 42(1):21–30

    Article  PubMed  CAS  Google Scholar 

  14. Dougall WC, Holen I, Gonzalez Suarez E (2014) Targeting RANKL in metastasis. BoneKey Rep 3:519

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hardcastle SA, Dieppe P, Gregson CL, Davey Smith G, Tobias JH (2015) Osteoarthritis and bone mineral density: are strong bones bad for joints? BoneKey Rep 4:624

    Article  PubMed  CAS  Google Scholar 

  16. Peel NF, Barrington NA, Blumsohn A, Colwell A, Hannon R, Eastell R (1995) Bone mineral density and bone turnover in spinal osteoarthrosis. Ann Rheum Dis 54(11):867–871

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Mackiewicz Z, Salo J, Konttinen YT, Kaigle Holm A, Indahl A, Pajarinen J, Holm S (2009) Receptor activator of nuclear factor kappa B ligand in an experimental intervertebral disc degeneration. Clin Exp Rheumatol 27(2):299–306

    PubMed  CAS  Google Scholar 

  18. Colombini A, Lombardi G, Corsi MM, Banfi G (2008) Pathophysiology of the human intervertebral disc. Int J Biochem Cell Biol 40(5):837–842

    Article  PubMed  CAS  Google Scholar 

  19. Colombini A, Brayda-Bruno M, Lombardi G, Croiset SJ, Vrech V, Maione V, Banfi G, Cauci S (2014) FokI Polymorphism in the vitamin D receptor gene (VDR) and its association with lumbar spine pathologies in the italian population: a case-control study. PLoS ONE 9(5):e97027

    Article  PubMed  PubMed Central  Google Scholar 

  20. Colombini A, Brayda-Bruno M, Ferino L, Lombardi G, Maione V, Banfi G, Cauci S (2015) Gender differences in the VDR-FokI polymorphism and conventional non-genetic risk factors in association with lumbar spine pathologies in an Italian case–control study. Int J Mol Sci 16(2):3722–3739

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Pike JW, Lee SM, Meyer MB (2014) Regulation of gene expression by 1,25-dihydroxy vitamin D3 in bone cells: exploiting new approaches and defining new mechanisms. BoneKey Rep 3:482

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gruber HE, Ingram JA, Hoelscher GL, Zinchenko N, Norton HJ, Hanley EN Jr (2011) Constitutive expression of cathepsin K in the human intervertebral disc: new insight into disc extracellular matrix remodeling via cathepsin K and receptor activator of nuclear factor-kappaB ligand. Arthritis Res Ther 13(4):R140

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Eswaran SK, Bevill G, Nagarathnam P, Allen MR, Burr DB, Keaveny TM (2009) Effects of suppression of bone turnover on cortical and trabecular load sharing in the canine vertebral body. J Biomech 42(4):517–523

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hernandez CJ, Tang SY, Baumbach BM, Hwu PB, Sakkee AN, van der Ham F, DeGroot J, Bank RA, Keaveny TM (2005) Trabecular microfracture and the influence of pyridinium and non-enzymatic glycation-mediated collagen cross-links. Bone 37(6):825–832

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Torkki M, Majuri ML, Wolff H, Koskelainen T, Haapea M, Niinimaki J, Alenius H, Lotz J, Karppinen J (2015) Osteoclast activators are elevated in intervertebral disks with Modic changes among patients operated for herniated nucleus pulposus. Eur Spine J [Epub ahead of print]

  26. Pye SR, Reid DM, Adams JE, Silman AJ, O’Neill TW (2007) Influence of weight, body mass index and lifestyle factors on radiographic features of lumbar disc degeneration. Ann Rheum Dis 66(3):426–427

    Article  PubMed  PubMed Central  Google Scholar 

  27. Battie MC, Videman T, Parent E (2004) Lumbar disc degeneration: epidemiology and genetic influences. Spine 29(23):2679–2690

    Article  PubMed  Google Scholar 

  28. Chung PL, Zhou S, Eslami B, Shen L, LeBoff MS, Glowacki J (2014) Effect of age on regulation of human osteoclast differentiation. J Cell Biochem 115(8):1412–1419

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Takeshita S, Fumoto T, Naoe Y, Ikeda K (2014) Age-related marrow adipogenesis is linked to increased expression of RANKL. J Biol Chem 289(24):16699–16710

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Khosla S (2013) Pathogenesis of age-related bone loss in humans. J Gerontol A Biol Sci Med Sci 68(10):1226–1235

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Meng YH, Li H, Chen X, Liu LB, Shao J, Chang KK, Du MR, Jin LP, Li MQ, Li DJ (2013) RANKL promotes the growth of decidual stromal cells in an autocrine manner via CCL2/CCR2 interaction in human early pregnancy. Placenta 34(8):663–671

    Article  PubMed  CAS  Google Scholar 

  32. Ma CJ, Liu X, Che LU, Liu ZH, Samartzis D, Wang HQ (2015) Stem cell therapies for intervertebral disc degeneration: immune privilege reinforcement by Fas/FasL regulating machinery. Curr Stem Cell Res Ther 10(4):285–295

    Article  PubMed  CAS  Google Scholar 

  33. Yamamoto J, Maeno K, Takada T, Kakutani K, Yurube T, Zhang Z, Hirata H, Kurakawa T, Sakai D, Mochida J, Doita M, Kurosaka M, Nishida K (2013) Fas ligand plays an important role for the production of pro-inflammatory cytokines in intervertebral disc nucleus pulposus cells. J Orthop Res 31(4):608–615

    Article  PubMed  CAS  Google Scholar 

  34. Sun Z, Wan ZY, Liu ZH, Guo YS, Yin JB, Duan CG, Gao Y, Li T, Wang HQ, Luo ZJ (2013) Expression of soluble Fas and soluble FasL in human nucleus pulposus cells. Int J Clin Exp Pathol 6(8):1567–1573

    PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors are indebted with Dr. Alessandro Degrate for his support in statistical analysis. This work has been partially supported by European Community’s Seventh Framework Programme (FP7, 2007–2013 under Grant Agreement No. HEALTHF2-2008-201626) and by the Italian Ministry of Health. The funder organizations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Experimental Biochemistry and Molecular Biology, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan, Italia

    Veronica Sansoni, Silvia Perego, Alessandra Colombini, Giuseppe Banfi & Giovanni Lombardi

  2. Vita-Salute San Raffaele University, Milan, Italia

    Giuseppe Banfi

  3. Scoliosis Unit, Department of Orthopedics and Traumatology-Spine Surgery III, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan, Italia

    Marco Brayda-Bruno

Authors
  1. Veronica Sansoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Perego
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandra Colombini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giuseppe Banfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marco Brayda-Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giovanni Lombardi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giovanni Lombardi.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sansoni, V., Perego, S., Colombini, A. et al. Interplay between low plasma RANKL and VDR-FokI polymorphism in lumbar disc herniation independently from age, body mass, and environmental factors: a case–control study in the Italian population. Eur Spine J 25, 192–199 (2016). https://doi.org/10.1007/s00586-015-4176-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-015-4176-7

Keywords

Search

Navigation