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European Spine Journal

, Volume 26, Issue 5, pp 1362–1373 | Cite as

ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes

  • Stefan Dudli
  • David C. Sing
  • Serena S. Hu
  • Sigurd H. Berven
  • Shane Burch
  • Vedat Deviren
  • Ivan Cheng
  • Bobby K. B. Tay
  • Todd F. Alamin
  • Ma Agnes Martinez Ith
  • Eric M. Pietras
  • Jeffrey C. Lotz
Original Article

Abstract

Study design

Cross-sectional cohort analysis of patients with Modic Changes (MC).

Objective

Our goal was to characterize the molecular and cellular features of MC bone marrow and adjacent discs. We hypothesized that MC associate with biologic cross-talk between discs and bone marrow, the presence of which may have both diagnostic and therapeutic implications.

Background data

MC are vertebral bone marrow lesions that can be a diagnostic indicator for discogenic low back pain. Yet, the pathobiology of MC is largely unknown.

Methods

Patients with Modic type 1 or 2 changes (MC1, MC2) undergoing at least 2-level lumbar interbody fusion with one surgical level having MC and one without MC (control level). Two discs (MC, control) and two bone marrow aspirates (MC, control) were collected per patient. Marrow cellularity was analyzed using flow cytometry. Myelopoietic differentiation potential of bone marrow cells was quantified to gauge marrow function, as was the relative gene expression profiles of the marrow and disc cells. Disc/bone marrow cross-talk was assessed by comparing MC disc/bone marrow features relative to unaffected levels.

Results

Thirteen MC1 and eleven MC2 patients were included. We observed pro-osteoclastic changes in MC2 discs, an inflammatory dysmyelopoiesis with fibrogenic changes in MC1 and MC2 marrow, and up-regulation of neurotrophic receptors in MC1 and MC2 bone marrow and discs.

Conclusion

Our data reveal a fibrogenic and pro-inflammatory cross-talk between MC bone marrow and adjacent discs. This provides insight into the pain generator at MC levels and informs novel therapeutic targets for treatment of MC-associated LBP.

Keywords

Modic change Cross-talk Pathobiology Bone marrow Neurotrophic Inflammation Myelopoiesis Osteoclastogenesis Fibrosis Pain 

Notes

Acknowledgements

This study was supported by the Swiss National Science Foundation Grant 145961, 158792, and 164726 as well as the National Institutes of Health Grant AR063705.

Conflict of interest

None of the authors has any potential conflict of interest.

Supplementary material

586_2017_4955_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 kb)
586_2017_4955_MOESM2_ESM.doc (218 kb)
Supplementary material 2 (DOC 218 kb)
586_2017_4955_MOESM3_ESM.pdf (241 kb)
Supplementary material 3 (PDF 240 kb)

References

  1. 1.
    Vos T, Flaxman AD, Naghavi M et al (2012) Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2163–2196CrossRefPubMedGoogle Scholar
  2. 2.
    Thompson KJ, Dagher AP, Eckel TS et al (2009) Modic changes on MR images as studied with provocative diskography: clinical relevance–a retrospective study of 2457 disks. Radiology 250(3):849–855CrossRefPubMedGoogle Scholar
  3. 3.
    Modic MT, Steinberg PM, Ross JS et al (1988) Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging. Radiology 166(1 Pt 1):193–199CrossRefPubMedGoogle Scholar
  4. 4.
    Jensen TS, Karppinen J, Sorensen JS et al (2008) Vertebral endplate signal changes (Modic change): a systematic literature review of prevalence and association with non-specific low back pain. Eur Spine J 17(11):1407–1422CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Luoma K, Vehmas T, Kerttula L et al (2016) Chronic low back pain in relation to Modic changes, bony endplate lesions, and disc degeneration in a prospective MRI study. Eur Spine J 25(9):2873–2881CrossRefPubMedGoogle Scholar
  6. 6.
    Jensen OK, Nielsen CV, Sørensen JS, Stengaard-Pedersen K (2014) Type 1 Modic changes was a significant risk factor for 1-year outcome in sick-listed low back pain patients: a nested cohort study using magnetic resonance imaging of the lumbar spine. Spine J 14(11):2568–2581CrossRefPubMedGoogle Scholar
  7. 7.
    Schistad EI, Espeland A, Rygh LJ et al (2014) The association between Modic changes and pain during 1-year follow-up in patients with lumbar radicular pain. Skeletal Radiol 43(9):1271–1279CrossRefPubMedGoogle Scholar
  8. 8.
    Järvinen J, Karppinen J, Niinimäki J et al (2015) Association between changes in lumbar Modic changes and low back symptoms over a two-year period. BMC Musculoskelet Disord 16(1):98CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ohtori S, Inoue G, Ito T 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(9):1026–1031CrossRefGoogle Scholar
  10. 10.
    Fields AJ, Liebenberg EC, Lotz JC (2014) Innervation of pathologies in the lumbar vertebral end plate and intervertebral disc. Spine J 14(3):513–521CrossRefPubMedGoogle Scholar
  11. 11.
    Dudli S, Fields AJ, Samartzis D et al (2016) Pathobiology of Modic changes. Eur Spine J 25(11):3723–3734CrossRefPubMedGoogle Scholar
  12. 12.
    Weiner BK, Vilendecic M, Ledic D et al (2015) Endplate changes following discectomy: natural history and associations between imaging and clinical data. Eur Spine J 24(11):2449–2457CrossRefPubMedGoogle Scholar
  13. 13.
    Schmid G, Witteler A, Willburger R et al (2004) Lumbar disk herniation: correlation of histologic findings with marrow signal intensity changes in vertebral endplates at MR imaging. Radiology 231(2):352–358CrossRefPubMedGoogle Scholar
  14. 14.
    Adams MA, Freeman BJ, Morrison HP et al (2000) Mechanical initiation of intervertebral disc degeneration. Spine (Phila. Pa. 1976) 25(13):1625–1636CrossRefGoogle Scholar
  15. 15.
    Ferguson SJ, Ito K, Nolte LP (2004) Fluid flow and convective transport of solutes within the intervertebral disc. J Biomech 37(2):213–221CrossRefPubMedGoogle Scholar
  16. 16.
    Rajasekaran S, Babu JN, Arun R et al (2004) ISSLS prize winner: a study of diffusion in human lumbar discs: a serial magnetic resonance imaging study documenting the influence of the endplate on diffusion in normal and degenerate discs. Spine (Phila. Pa. 1976) 29(23):2654–2667CrossRefGoogle Scholar
  17. 17.
    Torkki M, Majuri M-L, Wolff H et al (2016) Osteoclast activators are elevated in intervertebral disks with Modic changes among patients operated for herniated nucleus pulposus. Eur Spine J 25(1):207–216CrossRefPubMedGoogle Scholar
  18. 18.
    Burke J, Watson R, McCormack D et al (2003) Endplate changes are associated with increased disc inflammatory mediator production. J Bone Jt Surg Br 85-b(Supp II):164Google Scholar
  19. 19.
    Mirantes C, Passegué E, Pietras EM (2014) Pro-inflammatory cytokines: emerging players regulating HSC function in normal and diseased hematopoiesis. Exp Cell Res 329(2):248–254CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Schroeder GD, Markova DZ, Koerner JD et al (2016) Are modic changes associated with intervertebral disc cytokine profiles? Spine J 17(1):129–134CrossRefPubMedGoogle Scholar
  21. 21.
    Pietras EM, Mirantes-Barbeito C, Fong S et al (2016) Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol 18(6):607–618CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dudli S, Boffa DB, Ferguson SJ, Haschtmann D (2015) Leukocytes enhance inflammatory and catabolic degenerative changes in the intervertebral disc after endplate fracture in vitro without infiltrating the disc. Spine (Phila. Pa. 1976) 40(23):1799–1806CrossRefGoogle Scholar
  23. 23.
    Jensen TS, Bendix T, Sorensen JS et al (2009) Characteristics and natural course of vertebral endplate signal (Modic) changes in the Danish general population. BMC Musculoskelet Disord 10:81CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kaplanski G, Marin V, Montero-Julian F et al (2003) IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol 24(1):25–29CrossRefPubMedGoogle Scholar
  26. 26.
    Gabay C (2006) Interleukin-6 and chronic inflammation. Arthritis Res Ther 8(Suppl 2):S3CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ma L, Zhuang S (2011) The Role of STAT 3 in Tissue Fibrosis. Curr Chem Biol 5(1):44–51Google Scholar
  28. 28.
    Huebener P, Schwabe RF (2013) Regulation of wound healing and organ fibrosis by toll-like receptors. Biochim Biophys Acta Mol Basis Dis 1832(7):1005–1017CrossRefGoogle Scholar
  29. 29.
    Perilli E, Parkinson IH, Truong L-H et al (2014) Modic (endplate) changes in the lumbar spine: bone micro-architecture and remodelling. Eur Spine J 24(9):1926–1934CrossRefPubMedGoogle Scholar
  30. 30.
    Masson C (2011) Rheumatoid anemia. Jt Bone Spine 78(2):131–137CrossRefGoogle Scholar
  31. 31.
    Bober LA, Waters TA, Pugliese-Sivo CC et al (1995) IL-4 induces neutrophilic maturation of HL-60 cells and activation of human peripheral blood neutrophils. Clin Exp Immunol 99(1):129–136CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hu N, Qiu Y, Dong F (2015) Role of Erk1/2 signaling in the regulation of neutrophil versus monocyte development in response to G-CSF and M-CSF. J Biol Chem 290(40):24561–24573CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mossadegh-Keller N, Sarrazin S, Kandalla PK et al (2013) M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497(7448):239–243CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Si Y, Tsou C-L, Croft K et al (2010) CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice. J Clin Invest 120(4):1192–1203CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Labouyrie E, Dubus P, Groppi A et al (1999) Expression of neurotrophins and their receptors in human bone marrow. Am J Pathol 154(2):405–415CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ai L-S, Sun C-Y, Wang Y-D et al (2013) Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo. Int J Cancer 133(5):1074–1084CrossRefPubMedGoogle Scholar
  37. 37.
    Asaumi K, Nakanishi T, Asahara H et al (2000) Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone 26(6):625–633CrossRefPubMedGoogle Scholar
  38. 38.
    Kilian O, Hartmann S, Dongowski N et al (2014) BDNF and its TrkB receptor in human fracture healing. Ann Anat 196(5):286–295CrossRefPubMedGoogle Scholar
  39. 39.
    Su Y-W, Chung R, Ruan C-S et al (2016) Neurotrophin-3 Induces BMP-2 and VEGF activities and promotes the bony repair of injured growth plate cartilage and bone in rats. J Bone Miner Res 31(6):1258–1274CrossRefPubMedGoogle Scholar
  40. 40.
    Rezaee F, Rellick SL, Piedimonte G et al (2010) Neurotrophins regulate bone marrow stromal cell IL-6 expression through the MAPK pathway. PLoS One 5(3):e9690CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Rapp AE, Kroner J, Baur S et al (2015) Analgesia via blockade of NGF/TrkA signaling does not influence fracture healing in mice. J Orthop Res 33(8):1235–1241CrossRefPubMedGoogle Scholar
  42. 42.
    Ghilardi JR, Freeman KT, Jimenez-Andrade JM et al (2011) Sustained blockade of neurotrophin receptors TrkA, TrkB and TrkC reduces non-malignant skeletal pain but not the maintenance of sensory and sympathetic nerve fibers. Bone 48(2):389–398CrossRefPubMedGoogle Scholar
  43. 43.
    Iannone F, De Bari C, Dell’Accio F et al (2002) Increased expression of nerve growth factor (NGF) and high affinity NGF receptor (p140 TrkA) in human osteoarthritic chondrocytes. Rheumatology (Oxford) 41(12):1413–1418CrossRefGoogle Scholar
  44. 44.
    Nwosu LN, Mapp PI, Chapman V, Walsh DA (2015) Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis. Ann Rheum Dis 75(6):1246–1254CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    He Z, Ong CHP, Halper J, Bateman A (2003) Progranulin is a mediator of the wound response. Nat Med 9(2):225–229CrossRefPubMedGoogle Scholar
  46. 46.
    Zhao Y-P, Tian Q-Y, Liu B et al (2015) Progranulin knockout accelerates intervertebral disc degeneration in aging mice. Sci Rep 5:9102CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Stefan Dudli
    • 1
  • David C. Sing
    • 1
  • Serena S. Hu
    • 2
  • Sigurd H. Berven
    • 1
  • Shane Burch
    • 1
  • Vedat Deviren
    • 1
  • Ivan Cheng
    • 2
  • Bobby K. B. Tay
    • 1
  • Todd F. Alamin
    • 1
  • Ma Agnes Martinez Ith
    • 2
  • Eric M. Pietras
    • 3
  • Jeffrey C. Lotz
    • 1
  1. 1.Department of Orthopaedic SurgeryUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Stanford Spine ClinicStanford University Medical CenterStanfordUSA
  3. 3.Division of HematologyUniversity of Colorado DenverDenverUSA

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