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European Spine Journal
Published in: European Spine Journal 5/2017

01-05-2017 | Original Article

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

Authors: 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

Published in: European Spine Journal | Issue 5/2017

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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.
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Literature
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):2163–2196CrossRefPubMed
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):849–855CrossRefPubMed
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):193–199CrossRefPubMed
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):1407–1422CrossRefPubMedPubMedCentral
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):2873–2881CrossRefPubMed
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):2568–2581CrossRefPubMed
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):1271–1279CrossRefPubMed
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):98CrossRefPubMedPubMedCentral
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):1026–1031CrossRef
10.
Fields AJ, Liebenberg EC, Lotz JC (2014) Innervation of pathologies in the lumbar vertebral end plate and intervertebral disc. Spine J 14(3):513–521CrossRefPubMed
11.
Dudli S, Fields AJ, Samartzis D et al (2016) Pathobiology of Modic changes. Eur Spine J 25(11):3723–3734CrossRefPubMed
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):2449–2457CrossRefPubMed
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):352–358CrossRefPubMed
14.
Adams MA, Freeman BJ, Morrison HP et al (2000) Mechanical initiation of intervertebral disc degeneration. Spine (Phila. Pa. 1976) 25(13):1625–1636CrossRef
15.
Ferguson SJ, Ito K, Nolte LP (2004) Fluid flow and convective transport of solutes within the intervertebral disc. J Biomech 37(2):213–221CrossRefPubMed
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):2654–2667CrossRef
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):207–216CrossRefPubMed
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):164
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):248–254CrossRefPubMedPubMedCentral
20.
Schroeder GD, Markova DZ, Koerner JD et al (2016) Are modic changes associated with intervertebral disc cytokine profiles? Spine J 17(1):129–134CrossRefPubMed
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):607–618CrossRefPubMedPubMedCentral
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):1799–1806CrossRef
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 10:81CrossRefPubMedPubMedCentral
24.
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):25–29CrossRefPubMed
26.
27.
Ma L, Zhuang S (2011) The Role of STAT 3 in Tissue Fibrosis. Curr Chem Biol 5(1):44–51
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):1005–1017CrossRef
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):1926–1934CrossRefPubMed
30.
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):129–136CrossRefPubMedPubMedCentral
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):24561–24573CrossRefPubMedPubMedCentral
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):239–243CrossRefPubMedPubMedCentral
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):1192–1203CrossRefPubMedPubMedCentral
35.
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):1074–1084CrossRefPubMed
37.
Asaumi K, Nakanishi T, Asahara H et al (2000) Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone 26(6):625–633CrossRefPubMed
38.
Kilian O, Hartmann S, Dongowski N et al (2014) BDNF and its TrkB receptor in human fracture healing. Ann Anat 196(5):286–295CrossRefPubMed
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):1258–1274CrossRefPubMed
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):e9690CrossRefPubMedPubMedCentral
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):1235–1241CrossRefPubMed
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):389–398CrossRefPubMed
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):1413–1418CrossRef
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):1246–1254CrossRefPubMedPubMedCentral
45.
He Z, Ong CHP, Halper J, Bateman A (2003) Progranulin is a mediator of the wound response. Nat Med 9(2):225–229CrossRefPubMed
46.
Metadata
Title
ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes
Authors
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
Publication date
01-05-2017
Publisher
Springer Berlin Heidelberg
Published in
European Spine Journal / Issue 5/2017
Print ISSN: 0940-6719
Electronic ISSN: 1432-0932
DOI
https://doi.org/10.1007/s00586-017-4955-4

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