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

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.

Epidemiology of Modic changes in dogs: Prevalence, possible risk factors, and association with spinal phenotypes

“…Similarly as in humans, in low‐virulent or early stages of discospondylitis (bacterial discitis and osteomyelitis 43,44 ), MR signal intensity changes in the vertebrae can be encountered that resemble type 1 MCs 45,46 . Damage to the EPs is suggested to facilitate the development of MCs, as it promotes the interaction between IVD tissue and the vertebrae, thereby triggering an autoimmune response 15,28 . Interestingly, a significant association between vertebral EP changes detected on MRI and IVD disease of the adjacent disc was established in dogs, 47 indicating that dogs with IVD disease might also be prone to develop MCs.…”

“…Type 2 MCs (hyperintense on T1W and T2W) are believed to represent the conversion of normal into fatty bone marrow (together with increased reactive bone and granulation/fibrotic tissue infiltration). Activation of the complement system, an indication for inflammation, has been demonstrated in human MC2 specimens, which has been suggested to be linked to resorption of the disrupted EP 28 . Type 3 MCs (hypointense on T1W and T2W) are believed to represent subchondral bone sclerosis.…”

Cartilaginous endplates: A comprehensive review on a neglected structure in intervertebral disc research

“…Still, not all specimens with histopathological changes had MC on MRI. In another human cadaveric study, Heggli et al 125 showed that CEP and BEP damage are strongly associated with MC2. Supporting evidence for CEP damage in MC stems from studies assessing CEP fragments in surgically removed herniated disc tissue at the MC level.…”

“…120 Areas of vertebral endplate damage may trigger neoinnervation, [120][121][122] with concomitant bone marrow pathologies (MC) also shown to be innervated. 120,[123][124][125] While these sensory fibers generally terminate in or near the endosteal surface of the BEP, the CEP has also been shown…”

“…The evidence for innervation of the vertebral bone marrow extending to the endosteal surface gives a biological basis for the endplate as a source of nociception in vertebrogenic pain 120 . Areas of vertebral endplate damage may trigger neoinnervation, 120–122 with concomitant bone marrow pathologies (MC) also shown to be innervated 120,123–125 . While these sensory fibers generally terminate in or near the endosteal surface of the BEP, the CEP has also been shown to have small vascular spaces containing nerve fibers in some cases 121 and the CEP specifically can be accessed by nerves and blood vessels in the case of damage 126 …”