Skip to main content

Advertisement

SpringerLink
Log in

Osteoclast activators are elevated in intervertebral disks with Modic changes among patients operated for herniated nucleus pulposus

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

Abstract

Purpose

Modic changes (MC) are associated with low back pain (LBP). Inflammation is considered as a key factor that triggers symptoms in especially type I MC, but so far of the potential inflammatory candidates only TNFα has been linked to MC. The objective of the study was to analyze a set of inflammatory mediators in human surgical disk samples and quantify their association with MC in the adjacent vertebral bodies.

Methods

The study sample consisted of 51 intervertebral disk tissue specimens; 20 ‘No MC’ disks, 19 ‘Type I MC’ disks, and 12 ‘Type II MC’ disks. mRNA expression of 46 cytokines was quantified from isolated RNA. Tissue samples were stained using hematoxylin and eosin, toluidine blue, Herovici, CD68 and CD163.

Results

No significant differences were found in the amount of macrophages or presence of chondrocyte conglomerates between the MC groups. Of the multiple genes tested, statistically significant associations were observed for M-CSF1 (p = 0.028), RANKL (p = 0.035), RUNX1 (p = 0.032), and RUNX2 (p = 0.047) that were increased in ‘Type II MC,’ while OSCAR (p = 0.042) was increased in ‘Type I MC’ group compared to ‘No MC.’

Conclusions

Since these cytokines are related to differentiation and proliferation of osteoclasts, our data suggest that the stimulation of vertebral osteoclasts by factors secreted by disk tissue is involved in the pathophysiology of MC.

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

References

  1. Modic MT, Steinberg PM, Ross JS, Masaryk TJ, Carter JR (1988) Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging. Radiology 166:193–199

    Article  PubMed  CAS  Google Scholar 

  2. Kjaer P, Leboeuf-Yde C, Korsholm L, Sorensen JS, Bendix T (2005) Magnetic resonance imaging and low back pain in adults: a diagnostic imaging study of 40-year-old men and women. Spine (Phila Pa 1976) 30:1173–1180

    Article  Google Scholar 

  3. Kjaer P, Korsholm L, Bendix T, Sorensen JS, Leboeuf-Yde C (2006) Modic changes and their associations with clinical findings. Eur Spine J 15:1312–1319

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kuisma M, Karppinen J, Niinimäki J, Ojala R, Haapea M, Heliövaara M et al (2007) Modic changes in endplates of lumbar vertebral bodies: prevalence and association with low back and sciatic pain among middle-aged male workers. Spine (Phila Pa 1976) 32:1116–1122

    Article  Google Scholar 

  5. Kerttula L, Luoma K, Vehmas T, Grönblad M, Kääpä E (2012) Modic type I change may predict rapid progressive, deforming disc degeneration: a prospective 1-year follow-up study. Eur Spine J 21:1135–1142

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jensen T, Karppinen J, Sorensen J, Niinimäki J, Leboeuf-Yde C (2008) Vertebral endplate signal changes (Modic change): a systematic literature review of prevalence and association with non-specific low back pain. Eur Spine J17:1407–1422

    Article  Google Scholar 

  7. Ulrich J, Liebenberg E, Thuillier D, Lotz J (2007) ISSLS prize winner: repeated disc injury causes persistent inflammation. Spine (Phila Pa 1976) 32:2812–2819

    Article  Google Scholar 

  8. Ohtori S, Inoue G, Ito T, Koshi T, Ozawa T, Doya H et al (2006) Tumor necrosis factor-immunoreactive cells and PGP 9.5-immunoreactive nerve fibers in vertebral endplates of patients with discogenic low back Pain and Modic Type 1 or Type 2 changes on MRI. Spine (Phila Pa 1976) 31:1026–1031

    Article  Google Scholar 

  9. Karppinen J, Daavittila I, Solovieva S, Kuisma M, Taimela S, Natri A et al (2008) Genetic factors are associated with modic changes in endplates of lumbar vertebral bodies. Spine (Phila Pa 1976) 33:1236–1241

    Article  Google Scholar 

  10. Karppinen J, Solovieva S, Luoma K, Raininko R, Leino-Arjas P, Riihimäki H (2009) Modic changes and interleukin 1 gene locus polymorphisms in occupational cohort of middle-aged men. Eur Spine J 18:1963–1970

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kazakia GJ, Kuo D, Schooler J, Siddiqui S, Shanbhag S, Bernstein G et al (2013) Bone and cartilage demonstrate changes localized to bone marrow edema-like lesions within osteoarthritic knees. Osteoarthritis Cartilage 21:94–101

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N (2001) Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 26:1873–1878

    Article  CAS  Google Scholar 

  13. Määttä J, Kautiainen H, Leinonen V, Niinimäki J, Järvenpää S, Koskelainen T et al (2014) Association of Modic changes with health-related quality of life among patients referred to spine surgery. Scand J Pain 5:36–40

    Article  Google Scholar 

  14. Braithwaite I, White J, Saifuddin A, Renton P, Taylor BA (1998) Vertebral end-plate (Modic) changes on lumbar spine MRI: correlation with pain reproduction at lumbar discography. Eur Spine J 7:363–368

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Weishaupt D, Zanetti M, Hodler J, Min K, Fuchs B, Pfirrmann CW et al (2001) Painful lumbar disk derangement: relevance of endplate abnormalities at MR imaging. Radiology 218:420–427

    Article  PubMed  CAS  Google Scholar 

  16. Thompson KJ, Dagher AP, Eckel TS, Clark M, Reinig JW (2009) Modic changes on MR images as studied with provocative diskography: clinical relevance—a retrospective study of 2457 disks. Radiology 250:849–855

    Article  PubMed  Google Scholar 

  17. Kokkonen SM, Kurunlahti M, Tervonen O, Ilkko E, Vanharanta H (2002) Endplate degeneration observed on magnetic resonance imaging of the lumbar spine: correlation with pain provocation and disc changes observed on computed tomography diskography. Spine (Phila Pa 1976) 27:2274–2278

    Article  Google Scholar 

  18. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176

    Article  PubMed  CAS  Google Scholar 

  19. Quinn JM, Gillespie MT (2005) Modulation of osteoclast formation. Biochem Biophys Res Commun 328:739–745

    Article  PubMed  CAS  Google Scholar 

  20. Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E et al (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428:758–763

    Article  PubMed  CAS  Google Scholar 

  21. Hofbauer LC, Schoppet M (2004) Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 28(292):490–495

    Article  Google Scholar 

  22. Nakamura I, Takahashi N, Jimi E, Udagawa N, Suda T (2012) Regulation of osteoclast function. Mod Rheumatol 22:167–177

    Article  PubMed  Google Scholar 

  23. Kim JH, Kim K, Youn BU, Jin HM, Kim JY, Moon JB et al (2011) RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation. Biochem J 436:253–262

    Article  PubMed  CAS  Google Scholar 

  24. Gruber H, Ingram J, Hoelscher G, Zinchenko N, Norton HJ, Hanley E (2009) Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs. Arthritis Res Ther 11:R184

    Article  PubMed  PubMed Central  Google Scholar 

  25. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ (1999) Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 20:345–357

    Article  PubMed  CAS  Google Scholar 

  26. Choo MK, Yeo H, Zayzafoon M (2009) NFATc1 mediates HDAC-dependent transcriptional repression of osteocalcin expression during osteoblast differentiation. Bone 45:579–589

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Chen C, Cui L, Shang X, Zeng X (2010) NFAT regulates CSF-1 gene transcription triggered by L-selectin crosslinking. Biocell 34:57–63

    PubMed  CAS  Google Scholar 

  28. Kim N, Takami M, Rho J, Josien R, Choi Y (2002) A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med 195:201–209

    PubMed  CAS  PubMed Central  Google Scholar 

  29. Nemeth K, Schoppet M, Al-Fakhri N, Helas S, Jessberger R, Hofbauer LC et al (2011) The role of osteoclast-associated receptor in osteoimmunology. J Immunol 186:13–18

    Article  PubMed  CAS  Google Scholar 

  30. Herman S, Muller RB, Kronke G, Zwerina J, Redlich K, Hueber AJ et al (2008) Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis. Arthritis Rheum 58:3041–3050

    Article  PubMed  CAS  Google Scholar 

  31. Yamagata T, Maki K, Mitani K (2005) Runx1/AML1 in normal and abnormal hematopoiesis. Int J Hematol 82:1–8

    Article  PubMed  CAS  Google Scholar 

  32. Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T et al (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 35:341–348

    Article  PubMed  CAS  Google Scholar 

  33. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754

    Article  PubMed  CAS  Google Scholar 

  34. Zanatta M, Valenti MT, Donatelli L, Zucal C, Dalle Carbonare L (2012) Runx-2 gene expression is associated with age-related changes of bone mineral density in the healthy young-adult population. J Bone Miner Metab 30:706–714

    Article  PubMed  CAS  Google Scholar 

  35. Maruyama Z, Yoshida CA, Furuichi T, Amizuka N, Ito M, Fukuyama R et al (2007) Runx2 determines bone maturity and turnover rate in postnatal bone development and is involved in bone loss in estrogen deficiency. Dev Dyn 236:1876–1890

    Article  PubMed  CAS  Google Scholar 

  36. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR et al (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771

    Article  PubMed  CAS  Google Scholar 

  37. Martinez-Calatrava MJ, Prieto-Potin I, Roman-Blas JA, Tardio L, Largo R, Herrero-Beaumont G (2012) RANKL synthesized by articular chondrocytes contributes to juxta-articular bone loss in chronic arthritis. Arthritis Res Ther 14:R149

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Lotz J, Fields A, Liebenberg E (2013) The role of the vertebral end plate in low back pain. Global Spine J 3:153–164

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Wang F, Jiang JM, Deng CH, Wang FL, Fu ZZ, Zhang ZF (2011) Expression of Fas receptor and apoptosis in vertebral endplates with degenerative disc diseases categorized as Modic type I or II. Injury 42:790–795

    Article  PubMed  Google Scholar 

  40. Zanetti M, Bruder E, Romero J, Hodler J (2000) Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings. Radiology 215:835–840

    Article  PubMed  CAS  Google Scholar 

  41. Appel H, Loddenkemper C, Grozdanovic Z, Ebhardt H, Dreimann M, Hempfing A et al (2006) Correlation of histopathological findings and magnetic resonance imaging in the spine of patients with ankylosing spondylitis. Arthritis Res Ther 8:R143

    Article  PubMed  PubMed Central  Google Scholar 

  42. van Duivenvoorde LM, Dorris ML, Satumtira N, van Tok MN, Redlich K, Tak PP et al (2012) Relationship between inflammation, bone destruction, and osteoproliferation in the HLA-B27/human beta2 -microglobulin-transgenic rat model of spondylarthritis. Arthritis Rheum 64:3210–3219

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wu HL, Ding WY, Shen Y, Zhang YZ, Guo JK, Sun YP et al (2012) Prevalence of vertebral endplate modic changes in degenerative lumbar scoliosis and its associated factors analysis. Spine (Phila Pa 1976) 37:1958–1964

    Article  Google Scholar 

  44. Miyagi M, Ishikawa T, Kamoda H, Suzuki M, Murakami K, Shibayama M et al (2012) ISSLS prize winner: disc dynamic compression in rats produces long-lasting increases in inflammatory mediators in discs and induces long-lasting nerve injury and regeneration of the afferent fibers innervating discs: a pathomechanism for chronic discogenic low back pain. Spine (Phila Pa 1976) 37:1810–1818

    Article  Google Scholar 

  45. Lee S, Moon CS, Sul D, Lee J, Bae M, Hong Y et al (2009) Comparison of growth factor and cytokine expression in patients with degenerated disc disease and herniated nucleus pulposus. Clin Biochem 42:1504–1511

    Article  PubMed  CAS  Google Scholar 

  46. Richardson SM, Doyle P, Minogue BM, Gnanalingham K, Hoyland JA (2009) Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc. Arthritis Res Ther 11:R126

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We received funding from the AO Spine (Hansjörg Wyss Reward for Dr. Karppinen).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland

    Matias Torkki

  2. Unit of Systems Toxicology and Centre of Expertise for Health and Work Ability, Finnish Institute of Occupational Health, Helsinki, Finland

    Marja-Leena Majuri, Henrik Wolff & Harri Alenius

  3. Department of Neurosurgery, Oulu University Hospital, Oulu, Finland

    Tatu Koskelainen

  4. Institute of Diagnostics, Oulu University Hospital and University of Oulu, Oulu, Finland

    Marianne Haapea & Jaakko Niinimäki

  5. Department of Orthopaedic Surgery, University of California at San Francisco, San Francisco, CA, USA

    Jeffrey Lotz

  6. Centre of Expertise for Health and Work Ability, Occupational Health Services and Work Health, and Disability Prevention Centre, Finnish Institute of Occupational Health, Oulu, Finland

    Jaro Karppinen

  7. Centre for Life Course Epidemiology and Systems Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, PL 5000, Oulu, 90014, Oulu, Finland

    Jaro Karppinen

Authors
  1. Matias Torkki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marja-Leena Majuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henrik Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatu Koskelainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marianne Haapea
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jaakko Niinimäki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Harri Alenius
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jeffrey Lotz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jaro Karppinen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jaro Karppinen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torkki, M., Majuri, ML., Wolff, H. et al. Osteoclast activators are elevated in intervertebral disks with Modic changes among patients operated for herniated nucleus pulposus. Eur Spine J 25, 207–216 (2016). https://doi.org/10.1007/s00586-015-3897-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-015-3897-y

Keywords

Search

Navigation