Low back pain (LBP), as a leading cause of disability, is a common musculoskeletal disorder that results in major social and economic burdens. Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration, a significant contributor to LBP. Inflammatory mediators also play an indispensable role in discogenic LBP. The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies. Here, an overview of the advances in inflammation-related pain in disc degeneration is provided, with a discussion on the role of inflammation in IVD degeneration and pain induction. Puncture models, mechanical models, and spontaneous models as the main animal models to study painful disc degeneration are discussed, and the underlying signaling pathways are summarized. Furthermore, potential drug candidates, either under laboratory investigation or undergoing clinical trials, to suppress discogenic LBP by eliminating inflammation are explored. We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.

/pdf/painful-intervertebral-disc-degeneration-and-inflammation-2hn485rh6r.pdf

Painful intervertebral disc degeneration and inflammation: from laboratory evidence to clinical interventions.

Intervertebral disc (IVD) degeneration is a common finding on spine imaging that increases in prevalence with age. IVD degeneration is a frequent cause of low back pain, which is a leading cause of disability. The process of IVD degeneration consists of gradual structural change accompanied by severe alterations in metabolic homeostasis. IVD degeneration, like osteoarthritis, is a common comorbidity in patients with obesity and type 2 diabetes mellitus, two metabolic syndrome pathological conditions in which adipokines are important promoters of low-grade inflammation, extracellular matrix degradation and fibrosis. Impairment in white adipose tissue function, due to the abnormal fat accumulation in obesity, is characterized by increased production of specific pro-inflammatory proteins such as adipokines by white adipose tissue and of cytokines such as TNF by immune cells of the stromal compartment. Investigations into the immunometabolic alterations in obesity and type 2 diabetes mellitus and their interconnections with IVD degeneration provide insights into how adipokines might affect the pathogenesis of IVD degeneration and impair IVD function and repair. Toll-like receptor-mediated signalling has also been implicated as a promoter of the inflammatory response in the metabolic alterations associated with IVD and is thus thought to have a role in IVD degeneration. Pathological starvation, obesity and adipokine dysregulation can result in immunometabolic alterations, which could be targeted for the development of new therapeutics.

A new immunometabolic perspective of intervertebral disc degeneration.

The intervertebral disc (IVD) is the largest avascular organ of the body. It is composed of three parts: the nucleus pulposus (NP), the annulus fibrosus (AF) and the cartilaginous endplate (CEP). The central NP is surrounded by the AF and sandwiched by the two CEPs ever since its formation. This unique structure isolates the NP from the immune system of the host. Additionally, molecular factors expressed in IVD have been shown inhibitive effect on immune cells and cytokines infiltration. Therefore, the IVD has been identified as an immune privilege organ. The steady state of immune privilege is fundamental to the homeostasis of the IVD. The AF and the CEP, along with the immunosuppressive molecular factors are defined as the blood-NP barrier (BNB), which establishes a strong barrier to isolate the NP from the host immune system. When the BNB is damaged, the auto-immune response of the NP occurs with various downstream cascade reactions. This effect plays an important role in the whole process of IVD degeneration and related complications, such as herniation, sciatica and spontaneous herniated NP regression. Taken together, an enhanced understanding of the immune privilege of the IVD could provide new targets for the treatment of symptomatic IVD disease. However, the underlying mechanism above is still not fully clarified. Accordingly, the current study will extensively review and discuss studies regarding the immune privilege of the IVD.

/pdf/the-immune-privilege-of-the-intervertebral-disc-implications-eb5mtjc7g3.pdf

The Immune Privilege of the Intervertebral Disc: Implications for Intervertebral Disc Degeneration Treatment

Accumulating evidence has indicated that noncoding RNAs are involved in intervertebral disc degeneration (IDD); however, the competing endogenous RNA (ceRNA)‑mediated regulatory mechanisms in IDD remain rarely reported. The present study aimed to comprehensively investigate the alterations in expression levels of circular RNA (circRNA), long noncoding RNA (lncRNA), microRNA (miRNA/miR) and mRNA in the nucleus pulposus (NP) of patients with IDD. In addition, crucial lncRNA/circRNA‑miRNA‑mRNA ceRNA interaction axes were screened using the GSE67567 microarray dataset obtained from the Gene Expression Omnibus database. After data preprocessing, differentially expressed circRNAs (DECs), lncRNAs (DELs), miRNAs (DEMs) or genes (DEGs) between IDD and normal controls were identified using the Linear Models for Microarray data method. A protein‑protein interaction (PPI) network was constructed for DEGs based on protein databases, followed by module analysis. The ceRNA network was constructed based on the interaction between miRNAs and mRNAs, and lncRNAs/circRNAs and miRNAs. The underlying functions of mRNAs were predicted using the Database for Annotation, Visualization and Integrated Discovery database. The present study identified 636 DECs, 115 DELs, 84 DEMs and 1,040 DEGs between patients with IDD and control individuals. PPI network analysis demonstrated that Fos proto‑oncogene, AP‑1 transcription factor subunit (FOS), mitogen‑activated protein kinase 1 (MAPK1), hypoxia inducible factor 1 subunit α (HIF1A) and transforming growth factor β1 (TGFB1) were hub genes and enriched in modules. Metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1)/hsa_circRNA_102348‑hsa‑​miR‑185‑5p‑TGFB1/FOS, MALAT1‑hsa‑miR‑155‑5p‑HIF1A, hsa_circRNA_102399‑hsa‑miR‑302a‑3p‑HIF1A, MALAT1‑hsa‑​miR‑519d‑3p‑MAPK1 and hsa_circRNA_100086‑hsa‑miR‑509‑3p‑MAPK1 ceRNA axes were obtained by constructing the ceRNA networks. In conclusion, these identified ceRNA interaction axes may be crucial targets for the treatment of IDD.

/pdf/lncrna-circrna-mirna-mrna-cerna-network-in-lumbar-2s4g46s6uu.pdf

lncRNA/circRNA‑miRNA‑mRNA ceRNA network in lumbar intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) is a chronic, expensive, and high-incidence musculoskeletal disorder largely responsible for back/neck and radicular-related pain. It is characterized by progressive degenerative damage of intervertebral tissues along with metabolic alterations of all other vertebral tissues. Despite the high socio-economic impact of IVDD, little is known about its etiology and pathogenesis, and currently, no cure or specific treatments are available. Recent evidence indicates that besides abnormal and excessive mechanical loading, inflammation may be a crucial player in IVDD. Furthermore, obese adipose tissue is characterized by a persistent and low-grade production of systemic pro-inflammatory factors. In this context, chronic low-grade inflammation associated with obesity has been hypothesized as an important contributor to IVDD through different, but still unknown, mechanisms. Adipokines, such as leptin, produced prevalently by white adipose tissues, but also by other cells of mesenchymal origin, particularly cartilage and bone, are cytokine-like hormones involved in important physiologic and pathophysiological processes. Although initially restricted to metabolic functions, adipokines are now viewed as key players of the innate and adaptative immune system and active modulators of the acute and chronic inflammatory response. The goal of this review is to summarize the most recent findings regarding the interrelationships among inflammation, obesity and the pathogenic mechanisms involved in the IVDD, with particular emphasis on the contribution of adipokines and their potential as future therapeutic targets.

https://www.mdpi.com/1422-0067/20/8/2030/pdf

Molecular Relationships among Obesity, Inflammation and Intervertebral Disc Degeneration: Are Adipokines the Common Link?

Study design Rat nucleus pulposus (NP) cells or annulus fibrosus (AF) cells were stimulated with conditioned media of RAW 264.7 macrophages and vice versa under healthy culture conditions and in the presence of pro-inflammatory mediators. The gene expression of pro-inflammatory mediators, extracellular matrix (ECM)-modifying enzymes, and chemokines, which play important roles in intervertebral disc degeneration (IDD), was determined. Objective To test whether the interaction between native disc cells and infiltrating macrophages accelerates inflammation state, disrupts matrix homeostasis, and promotes inflammatory cells infiltration. Summary of background data With macrophages infiltration, the disc resident cells would be inevitably exposed to macrophages. Macrophages have been shown to play pro-inflammatory role in the cellular interactions with disc cells under healthy culture conditions. However, the biologic interactions between macrophages and disc cells under degenerated disc inflammatory environment remain unknown. Methods Murine Macrophages RAW 264.7 were cultured in the conditioned media of Rat AF or NP cells culture in the presence or absence of IL-1β stimulation. Similarly, Rat AF or NP cells were also cultured in the conditioned media of Murine Macrophages RAW 264.7 culture in the presence or absence of IFN-γ stimulation. The mRNA levels difference of pro-inflammatory genes, catabolic genes and chemokines genes for AF cells, NP cells and Macrophages RAW 264.7 were analyzed by qRT-PCR, respectively. Results Compared with serum-free media exposure, RAW 264.7 macrophages exposed to AF or NP cells conditioned media selectively modestly upregulated mRNA levels of the aforementioned cytokines. Exposure of RAW 264.7 macrophages to conditioned media from AF or NP cells with IL-1β stimulation dramatically increased mRNA levels of all the investigated cytokines. Similarly, compared with serum-free media exposure, AF or NP cells exposed to RAW 264.7 macrophages conditioned media selectively modestly upregulated mRNA levels of the aforementioned cytokines. Exposure of AF or NP cells to conditioned media from RAW 264.7 macrophages with IFN-γ stimulation dramatically increased mRNA levels of all the investigated cytokines. Conclusion The biologic interactions between infiltrating macrophages and native disc cells under degenerated disc inflammatory environment lead to an increasingly severe inflammatory conditions, which may be a self-stimulated process from the macrophages infiltration occurrenceLevel of Evidence: 5.

Secreted Factors From Intervertebral Disc Cells and Infiltrating Macrophages Promote Degenerated Intervertebral Disc Catabolism.

Study design Rat nucleus pulposus (NP) cells were activated with resistin with or without p38 mitogen-activated protein kinase (MAPK) pathway inhibition. The expression of a disintegrin and metalloprotease with thrombospondin motif-5 (ADAMTS-5), which plays an important role in intervertebral disc degeneration (IDD), was determined. Objective The aim of this study was to demonstrate whether resistin can influence the ADAMTS-5 expression and to further investigate the underlying mechanisms. Summary of background data Obesity has been demonstrated to promote IDD, whereas the exact mechanism remains poorly understood. Resistin, as an important adipokine, is increased with obesity and has been shown to play pro-inflammatory and catabolic role in cartilage metabolism. However, the effect of resistin on the catabolic enzymes within NP cells remains unknown. Methods We exposed NP cells to resistin, and the transcriptional activity, gene expression, and protein levels of ADAMTS-5 were measured by luciferase reporter assay, qRT-polymerase chain reaction, immunofluorescence, and western blot, respectively. The activation of p38 MAPK pathways was detected using western blot analysis. Results Resistin had no effect on cell viability. Resistin increased ADAMTS-5 expression in rat NP cells time and dose dependently. The p38 MAPK signaling pathway was activated after exposure to resistin. Treatment with p38 inhibitor decreased the upregulation of ADAMTS-5 by resistin. Conclusion The current study, for the first time, investigated the role of resistin in ADAMTS-5 regulation in IDD. These findings provide novel evidence supporting the causative role of obesity in IDD, which is important to develop novel preventative or therapeutic treatment in disc degenerative disorders. Level of evidence N/A.

Resistin Promotes Intervertebral Disc Degeneration by Upregulation of ADAMTS-5 Through p38 MAPK Signaling Pathway.

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Secreted Factors From Intervertebral Disc Cells and Infiltrating Macrophages Promote Degenerated Intervertebral Disc Catabolism.

Resistin Promotes Intervertebral Disc Degeneration by Upregulation of ADAMTS-5 Through p38 MAPK Signaling Pathway.