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

Irina Heggli; Christoph J Laux; Tamara Mengis; Agnieszka Karol; Frédéric Cornaz; Nick Herger; Borbala Aradi-Vegh; Jonas Widmer; Marco D Burkhard; Nadja A Farshad-Amacker; Sibylle Pfammatter; Witold E Wolski; Florian Brunner; Oliver Distler; Mazda Farshad; Stefan Dudli

doi:10.1002/jsp2.1237

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

JOR Spine. 2022 Dec 23;6(1):e1237. doi: 10.1002/jsp2.1237. eCollection 2023 Mar.

Authors

Irina Heggli¹, Christoph J Laux², Tamara Mengis¹, Agnieszka Karol³, Frédéric Cornaz², Nick Herger¹, Borbala Aradi-Vegh¹, Jonas Widmer², Marco D Burkhard², Nadja A Farshad-Amacker⁴, Sibylle Pfammatter⁵, Witold E Wolski^{5

6}, Florian Brunner⁷, Oliver Distler¹, Mazda Farshad², Stefan Dudli¹

Affiliations

¹ Center of Experimental Rheumatology, Balgrist Campus, University Hospital Zurich and Balgrist University Hospital, University of Zurich Zurich Switzerland.
² Department of Orthopedics, Balgrist University Hospital University of Zurich Zurich Switzerland.
³ Department of Molecular Mechanisms of Disease University of Zurich Zurich Switzerland.
⁴ Department of Radiology Balgrist University Hospital, University of Zurich Zurich Switzerland.
⁵ Functional Genomics Center Zurich, University and ETH Zurich Zurich Switzerland.
⁶ Swiss Institute of Bioinformatics Lausanne Switzerland.
⁷ Department of Physical Medicine and Rheumatology Balgrist University Hospital, University of Zurich Zurich Switzerland.

Abstract

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.

Keywords: degeneration; extracellular matrix; immune response; inflammation.