BackgroundMany intervertebral disc diseases cause low back pain (LBP). Proinflammatory cytokines and matrix metalloproteinases (MMPs) participate in disc pathology. In this study, we examined levels of serum cytokines and MMPs in human subjects with diagnoses of disc herniation (DH), spinal stenosis (SS), or degenerative disc disease (DDD) relative to levels in control subjects. Comparison between subjects with DH and those with other diagnoses (Other Dx, grouped from SS and DDD) was performed to elaborate a pathological mechanism based on circulating cytokine levels.MethodsStudy participants were recruited from a spine neurosurgery practice (n = 80), a back pain management practice (n = 27), or a control cohort (n = 26). Serum samples were collected before treatment and were assayed by multiplex assays for levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ, tumor necrosis factor-α, MMP-1, MMP-3, and MMP-9. Inflammatory and degradative mediator levels were compared for subjects with LBP and control subjects, by diagnosis and by treatment groups, controlling for effects of sex, age, and reported history of osteoarthritis. Spearman’s correlation coefficient was used to examine relationships with age, body mass index (BMI), symptom duration, and smoking history.ResultsSerum levels of IL-6 were significantly higher in subjects with LBP compared with control subjects. Participants with LBP due to Other Dx had significantly higher levels of IL-6 than DH and controls. Serum levels of MMP-1 were significantly lower in LBP subjects, specifically those with DH, than in control subjects. Positive correlations were found between IL-6 levels and BMI, symptom duration, and age. MMP-1 levels were positively correlated with age.ConclusionsThe findings of the present clinical study are the results of the first examination of circulating cytokine levels in DDD and SS and provide evidence for a more extensive role of IL-6 in disc diseases, where patients with DDD or SS have higher serum cytokine levels than those with DH or control subjects. These findings suggest that LBP subjects have low-grade systemic inflammation, and biochemical profiling of circulating cytokines may assist in refining personalized diagnoses of disc diseases.

Intervertebral disc (IVD) degeneration (DD) is associated with low back pain, the leading cause of disability worldwide. Damage‐associated molecular patterns (DAMPs) that contribute to inflammation and trigger DD have not been well characterized. Extracellular high mobility group box‐1 (HMGB1) protein has been implicated as a potent DAMP and pro‐inflammatory stimulus in the immune system. In this study, we show that HMGB1 and IL‐6 levels increase in patients with advanced DD in comparison to early DD. This study further tested the hypothesis that HMGB1 promotes inflammatory signaling driving DD in human nucleus pulposus (NP) cells and tissue. Immunofluorescence and western blot analysis confirmed the expression of HMGB1 and its extracellular release by NP cells under cell stress. Gene expression and protein quantification indicate that HMGB1 stimulates the expression IL‐6 and MMP‐1 in a dose‐dependent manner. The contributions of toll‐like receptor (TLR) −2, −4 and receptor for advanced glycation end products (RAGE) as receptors mediating HMGB1 signaling was examined using small molecule inhibitors. Inhibition of TLR‐4 signaling, with TAK‐242, completely abrogated HMGB1 induced IL‐6 and MMP‐1 expression, whereas inhibition of TLR‐2, with O‐vanillin, or RAGE, with FPS‐ZM1, had mild inhibitory effects. HMGB1 stimulation activated NF‐ĸB signaling while TAK‐242 co‐treatment abrogated it. Lastly, effects of HMGB1 on matrix deposition was evaluated in a 3D culture system of human NP cells. These results implicate HMGB1 as a potent DAMP that promotes inflammation in NP cells and degradation of NP tissues. TLR4‐HMGB1 axis is a potential major pathway to alleviate disc inflammation and mitigate DD. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Molecular events that drive disc damage and low back pain (LBP) may precede clinical manifestation of disease onset and can cause detrimental long-term effects such as disability. Biomarkers serve as objective molecular indicators of pathological processes. The goal of this study is to identify systemic biochemical factors as predictors of response to treatment of LBP with epidural steroid injection (ESI). Since inflammation plays a pivotal role in LBP, this pilot study investigates the effect of ESI on systemic levels of 48 inflammatory biochemical factors (cytokines, chemokines, and growth factors) and examines the relationship between biochemical factor levels and pain or disability in patients with disc herniation (DH), or other diagnoses (Other Dx) leading to low back pain, which included spinal stenosis (SS) and degenerative disc disease (DDD). Study participants (n = 16) were recruited from a back pain management practice. Pain numerical rating score (NRS), Oswestry Disability Index (ODI), and blood samples were collected pre-and at 7 to 10 days post-treatment. Blood samples were assayed for inflammatory mediators using commercial multiplex assays. Mediator levels were compared pre-and post-treatment to investigate the potential correlations between clinical and biochemical outcomes. Our results indicate that a single ESI significantly decreased systemic levels of SCGF-b and IL-2. Improvement in pain in all subjects was correlated with changes in chemokines (MCP-1, MIG), hematopoietic progenitor factors (SCGF-b), and factors that participate in angiogenesis/fibrosis (HGF), nociception (SCF, IFN-a2), and inflammation (IL-6, IL-10, IL-18, TRAIL). Levels of biochemical mediators varied based on diagnosis of LBP, and changes in pain responses and systemic mediators from pre-to post-treatment were dependent on the diagnosis cohort. In the DH cohort, levels of IL-17 and VEGF significantly decreased post-treatment. In the Other Dx cohort, levels of IL-2Ra, IL-3, and SCGF-b significantly decreased post-treatment. In order to determine whether mediator changes were related to pain, correlations between change in pain scores and change in mediator levels were performed. Subjects with DH demonstrated a profile signature that implicated hematopoiesis factors (SCGF-b, GM-CSF) in pain response, while subjects with Other Dx demonstrated a biomarker profile that implicated chemokines (MCP-1, MIG) and angiogenic factors (HGF, VEGF) in pain response. Our findings provide evidence that systemic biochemical factors in patients with LBP vary by diagnosis, and pain response to treatment is associated with a unique profile of biochemical responses in each diagnosis group. Future hypothesis-based studies with larger subject cohorts are warranted to confirm the findings of this pilot exploratory study.

Low back pain is a leading cause of disability worldwide and the second most common cause of physician visits. There are many causes of back pain, and among them, disc herniation and intervertebral disc degeneration are the most common diagnoses and targets for intervention. Currently, clinical treatment outcomes are not strongly correlated with diagnoses, emphasizing the importance for characterizing more completely the mechanisms of degeneration and their relationships with symptoms. This review covers recent studies elucidating cellular and molecular changes associated with disc mechanobiology, as it relates to degeneration and regeneration. Specifically, we review findings on the biochemical changes in disc diseases, including cytokines, chemokines, and proteases; advancements in disc disease diagnostics using imaging modalities; updates on studies examining the response of the intervertebral disc to injury; and recent developments in repair strategies, including cell-based repair, biomaterials, and tissue engineering. Findings on the effects of the omega-6 fatty acid, linoleic acid, on nucleus pulposus tissue engineering are presented. Studies described in this review provide greater insights into the pathogenesis of disc degeneration and may define new paradigms for early or differential diagnostics of degeneration using new techniques such as systemic biomarkers. In addition, research on the mechanobiology of disease enriches the development of therapeutics for disc repair, with potential to diminish pain and disability associated with disc degeneration.