CD90-positive stromal cells associate with inflammatory and fibrotic changes in modic changes

Dudli, Stefan; Karol, Agnieszka; Giudici, Luca; Heggli, I.; Laux, Christoph J.; Spirig, José Miguel; Wanivenhaus, Florian; Betz, Michael; Germann, Christoph; Farshad‐Amacker, Nadja A.; Brunner, Florian; Distler, Oliver; Farshad, Mazda

doi:10.1016/j.ocarto.2022.100287

Cited by 13 publications

(33 citation statements)

References 32 publications

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“…unknown, yet experimental endplate fractures in a rabbit ex-vivo explant model has been shown to induce the release of LDH, potentially from endplate and disc cells 33 . In MC1, endplates are damaged, and the discs are degenerated (Table 2) 34 . Our findings indicate that tissue destruction in MC1 is not limited to an initiating event but is a chronic mechanism in MC1.…”

Section: Discussionmentioning

confidence: 99%

Role of C‐reactive protein in the bone marrow of Modic type 1 changes

Dudli

Heggli

Laux

et al. 2022

Journal Orthopaedic Research

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Modic type 1 changes (MC1) are vertebral bone marrow lesions and associate with low back pain. Increased serum C-reactive protein (CRP) has inconsistently been associated with MC1. We aimed to provide evidence for a role of CRP in the tissue pathophysiology of MC1 bone marrow. From thirteen MC1 patients undergoing spinal fusion at MC1 levels, vertebral bone marrow aspirates from MC1 and intra-patient control bone marrow were taken. Bone marrow CRP, IL-1, and IL-6 were measured with enzyme-linked immunosorbent assays; lactate dehydrogenase (LDH) was measured with a colorimetric assay. CRP, IL-1, and IL-6 were compared between MC1 and control bone marrow. Bone marrow CRP was correlated with blood CRP and with bone marrow IL-1, IL-6, and LDH. CRP expression by marrow cells was measured with PCR. Increased CRP in MC1 bone marrow (mean difference: +0.22 mg CRP/g protein, 95% CI [-0.04, 0.47], p=0.088) correlated with blood CRP (r=0.69, p=0.018), with bone marrow IL-1 (=0.52, p=0.029) and IL-6 (=0.51, p=0.031). Marrow cells did not express CRP. Increased LDH in MC1 bone marrow (143.1%, 95% CI [110.7%, 175.4%], p=0.014) indicated necrosis. A blood CRP threshold of 3.2 mg/L detected with 100% accuracy increased CRP in MC1 bone marrow. In conclusion, the association of CRP with inflammatory and necrotic changes in MC1 bone marrow provides evidence for a pathophysiological role of CRP in MC1 bone marrow.

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Section: Discussionmentioning

confidence: 99%

Role of C‐reactive protein in the bone marrow of Modic type 1 changes

Dudli

Heggli

Laux

et al. 2022

Journal Orthopaedic Research

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“…Second, even if fibrotic features such as ECM gene expression, cell-matrix adhesion and integrin expression of MC1 BMCS were analysed, the pro-fibrotic phenotype would not have been revealed (Awan et al, 2018;Grella et al, 2016;Herrera et al, 2018;Thannickal et al, 2003). Hence, it would have not been possible to conclude that MC1 BMSCs with FGF2 have a pro-fibrotic phenotype, which is not in agreement with the current understanding of MC1 pathophysiology (Dudli et al, 2020;Dudli et al, 2022;Heggli et al, 2021;Modic et al, 1988).…”

Section: Discussionmentioning

confidence: 93%

“…According to their appearance on MRI, three interconvertible types of MC are distinguished: MC1 (T1w: hypointense, T2w: hyperintense), MC2 (T1w and T2w: hyperintense) and MC3 (T1w and T2w: hypointense). A few histological studies have shown inflammation, fibrosis and high bone turnover in MC1, increased bone erosion and fatty replacement of normal bone marrow in MC2, and a stable sclerotic state in MC3 (Dudli et al, 2016;2022). Despite the high prevalence of MC, the pathobiology is poorly understood and an MC-specific treatment does not exist (Jensen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Of the three types, MC1 have the largest association with non-specific chronic LBP (Mera et al, 2021;Saukkonen et al, 2020) and were, therefore, the focus of a previous pathomechanistic study (Heggli et al, 2021). Fibrosis is an important hallmark of the MC1 pathomechanism and is a potential candidate when selecting MC1 serum biomarkers (Dudli et al, 2016;2022;Modic et al, 1988). Fibrosis in MC1 seems to be mediated by BMSCs.…”

Section: Introductionmentioning

confidence: 99%

“…Fibrosis in MC1 seems to be mediated by BMSCs. CD90 is an important BMSC marker and MC1 bone marrow biopsies have more CD90 + cells, which correlates with fibrotic changes (Dudli et al, 2022). Furthermore, MC1 BMSCs have a pro-fibrotic transcriptome, secrete more ECM and have a stronger adherence to their matrix as well as a higher contractile capacity (Heggli et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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FGF2 overrides key pro-fibrotic features of bone marrow stromal cells isolated from Modic type 1 change patients

Heggli¹,

Blache²,

Herger³

et al. 2022

eCM

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Extensive extracellular matrix production and increased cell-matrix adhesion by bone marrow stromal cells (BMSCs) are hallmarks of fibrotic alterations in the vertebral bone marrow known as Modic type 1 changes (MC1). MC1 are associated with non-specific chronic low-back pain. To identify treatment targets for MC1, in vitro studies using patient BMSCs are important to reveal pathological mechanisms. For the culture of BMSCs, fibroblast growth factor 2 (FGF2) is widely used. However, FGF2 has been shown to suppress matrix synthesis in various stromal cell populations. The aim of the present study was to investigate whether FGF2 affected the in vitro study of the fibrotic pathomechanisms of MC1-derived BMSCs. Transcriptomic changes and changes in cell-matrix adhesion of MC1-derived BMSCs were compared to intra-patient control BMSCs in response to FGF2. RNA sequencing and quantitative real-time polymerase chain reaction revealed that pro-fibrotic genes and pathways were not detectable in MC1-derived BMSCs when cultured in the presence of FGF2. In addition, significantly increased cell-matrix adhesion of MC1-derived BMSCs was abolished in the presence of FGF2. In conclusion, the data demonstrated that FGF2 overrides key pro-fibrotic features of MC1 BMSCs in vitro. Usage of FGF2-supplemented media in studies of fibrotic mechanisms should be critically evaluated as it could override normally dominant biological and biophysical cues.

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Modic type 2 changes are fibroinflammatory changes with complement system involvement adjacent to degenerated vertebral endplates

et al. 2022

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Background Vertebral endplate signal intensity changes visualized by magnetic resonance imaging termed Modic changes (MC) are highly prevalent in low back pain patients. Interconvertibility between the three MC subtypes (MC1, MC2, MC3) suggests different pathological stages. Histologically, granulation tissue, fibrosis, and bone marrow edema are signs of inflammation in MC1 and MC2. However, different inflammatory infiltrates and amount of fatty marrow suggest distinct inflammatory processes in MC2. Aims The aims of this study were to investigate (i) the degree of bony (BEP) and cartilage endplate (CEP) degeneration in MC2, (ii) to identify inflammatory MC2 pathomechanisms, and (iii) to show that these marrow changes correlate with severity of endplate degeneration. Methods Pairs of axial biopsies (n = 58) spanning the entire vertebral body including both CEPs were collected from human cadaveric vertebrae with MC2. From one biopsy, the bone marrow directly adjacent to the CEP was analyzed with mass spectrometry. Differentially expressed proteins (DEPs) between MC2 and control were identified and bioinformatic enrichment analysis was performed. The other biopsy was processed for paraffin histology and BEP/CEP degenerations were scored. Endplate scores were correlated with DEPs. Results Endplates from MC2 were significantly more degenerated. Proteomic analysis revealed an activated complement system, increased expression of extracellular matrix proteins, angiogenic, and neurogenic factors in MC2 marrow. Endplate scores correlated with upregulated complement and neurogenic proteins. Discussion The inflammatory pathomechanisms in MC2 comprises activation of the complement system. Concurrent inflammation, fibrosis, angiogenesis, and neurogenesis indicate that MC2 is a chronic inflammation. Correlation of endplate damage with complement and neurogenic proteins suggest that complement system activation and neoinnervation may be linked to endplate damage. The endplate-near marrow is the pathomechanistic site, because MC2 occur at locations with more endplate degeneration. Conclusion MC2 are fibroinflammatory changes with complement system involvement which occur adjacent to damaged endplates.

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CD90-positive stromal cells associate with inflammatory and fibrotic changes in modic changes

Cited by 13 publications

References 32 publications

Role of C‐reactive protein in the bone marrow of Modic type 1 changes

Role of C‐reactive protein in the bone marrow of Modic type 1 changes

FGF2 overrides key pro-fibrotic features of bone marrow stromal cells isolated from Modic type 1 change patients

Modic type 2 changes are fibroinflammatory changes with complement system involvement adjacent to degenerated vertebral endplates

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