Evidence for a Role of Nerve Injury in Painful Intervertebral Disc Degeneration: A Cross-Sectional Proteomic Analysis of Human Cerebrospinal Fluid

Abstract

Intervertebral disc degeneration (DD) is a cause of low back pain (LBP) in some individuals. However, while >30% of adults have DD, LBP only develops in a subset of individuals. To gain insight into the mechanisms underlying non-painful versus painful DD, human cerebrospinal fluid (CSF) was examined using differential expression shotgun proteomic techniques comparing healthy controls, subjects with non-painful DD, and patients with painful DD scheduled for spinal fusion surgery. Eighty-eight proteins were detected, 27 of which were differentially expressed. Proteins associated with DD tended to be related to inflammation (e.g. cystatin C) regardless of pain status. In contrast, most differentially expressed proteins in DD-associated chronic LBP patients were linked to nerve injury (e.g. hemopexin). Cystatin C and hemopexin were selected for further examination by ELISA in a larger cohort. While Cystatin C correlated with DD severity but not pain or disability, hemopexin correlated with pain intensity, physical disability and DD severity. This study demonstrates that CSF can be used to study mechanisms underlying painful DD in humans, and suggests that while painful DD is associated with nerve injury, inflammation itself is not sufficient to develop LBP.

Proteomic studies of common chronic pain conditions - a systematic review and associated network analyses

“…Lim et al -comparing CSF samples of patients with low back pain (LBP) with disc degeneration (DD), 1 pain-free controls with DD, and healthy controls without DD -found 12 proteins that were significantly altered in LBP with DD [95]. Eight proteins were uniquely altered in painful DD but not in pain-free patients versus healthy controls: proSAAS, hemopexin, prosaposin, beta- [75,76,89].…”

“…The significant PPI enrichment analysis (P-value < 1.0e-16) of altered proteins in CSF from patients with low back pain compared to healthy controls grouped the identified proteins as transport proteins ( Supplementary Figure 4) [95]. These extracellular proteins have molecular functions connected to cholesterol regulation, enzyme regulator activity, and meta ion and protein binding.…”

“…Lim et al -analyzing CSF samples between LBP with disc degeneration (DD), pain free controls with DD, and healthy controls without DD -found a correlation between Cystain C and severity of DD and a correlation between hemopexin and DD severity, pain intensity, and pain experience (McGill Pain Questionnaire (MPQ)) and disability (Oswestry Disability Index (ODI)) [95].…”

“…Generally, the studies compared one diagnosis with healthy controls. Although several pain diagnoses can identify which changes are general and which are specific, few studies included more than one pain group [74,76,79,81,90,95].…”

Low back pain: Moving toward mechanism-based management

“…TNF-Alpha in nucleus pulposus and interleukins may induce this sensory nerve growth (Hayashi et al, 2008). There is also evidence of association between painful intervertebral disc degeneration and nerve injury (Lim et al, 2017). Inflammatory factors.…”