Fas ligand plays an important role for the production of pro‐inflammatory cytokines in intervertebral disc nucleus pulposus cells

Yamamoto, Junya; Maeno, Kazuo; Takada, Toru; Kakutani, Kenichiro; Yurube, Takashi; Zhang, Zhongying; Harai, Hiroaki; Kurakawa, Takuto; Sakai, Daisuke; Mochida, Joji; Doita, Minoru; Kurosaka, Masahiro; Nishida, Kotaro

doi:10.1002/jor.22274

Cited by 57 publications

(43 citation statements)

References 23 publications

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“…This is in agreement with findings in herniated and degenerated discs [63, 67]. In addition, NP cells elicit a primary immune response in macrophages and natural killer cells [68, 69]. Disc ECM is also linked to immunity, as disc proteoglycans can enhance lymphocyte transformation in vitro [65] and mice immunized with cartilage proteoglycans show strong mononuclear cell infiltration into the disc and almost completely resorbed discs [70].…”

Section: Etiopathogenesis Of Modic Changessupporting

confidence: 84%

Pathobiology of Modic changes

et al. 2016

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Purpose Low back pain (LBP) is the most disabling condition worldwide. Although LBP relates to different spinal pathologies, vertebral bone marrow lesions visualized as Modic changes on MRI have a high specificity for discogenic LBP. This review summarizes the pathobiology of Modic changes and suggests a disease model. Methods Non-systematic literature review. Results Chemical and mechanical stimulation of nociceptors adjacent to damaged endplates are likely a source of pain. Modic changes are adjacent to a degenerated intervertebral disc and have three generally interconvertible types suggesting that the different Modic change types represent different stages of the same pathological process, which is characterized by inflammation, high bone turnover, and fibrosis. A disease model is suggested where disc/ endplate damage and the persistence of an inflammatory stimulus (i.e., occult discitis or autoimmune response against disc material) create predisposing conditions. The risk to develop Modic changes likely depends on the inflammatory potential of the disc and the capacity of the bone marrow to respond to it. Bone marrow lesions in osteoarthritic knee joints share many characteristics with Modic changes adjacent to degenerated discs and suggest that damage-associated molecular patterns and marrow fat metabolism are important pathogenetic factors. There is no consensus on the ideal therapy. Non-surgical treatment approaches including intradiscal steroid injections, anti-TNF-α antibody, antibiotics, and bisphosphonates have some demonstrated efficacy in mostly non-replicated clinical studies in reducing Modic changes in the short term, but with unknown long-term benefits. New diagnostic tools and animal models are required to improve painful Modic change identification and classification, and to clarify the pathogenesis. Conclusion Modic changes are likely to be more than just a coincidental imaging finding in LBP patients and rather represent an underlying pathology that should be a target for therapy.

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Section: Etiopathogenesis Of Modic Changessupporting

confidence: 84%

Pathobiology of Modic changes

et al. 2016

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“…While the relative importance of each of these factors is currently unknown they all lead to a common disease phenotype: loss of water signal on T2 weighted MRI referred to as a “black disc”, together with some degree of inflammation, and bulging of herniation of the NP (Figure 1). Degeneration is thought to be mediated by the abnormal production of pro-inflammatory molecules secreted by both the nucleus pulposus (NP) and annulus fibrosus (AF) (the fibrocartilagenous tissue that contains the NP) cells as well macrophages, T cells and neutrophils 15–17 . These cytokines trigger a range of pathogenic responses by the disc cells that can promote autophagy, senescence and apoptosis 8,18,19 .…”

Section: Introductionmentioning

confidence: 99%

Role of cytokines in intervertebral disc degeneration: pain and disc content

2013

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Degeneration of the intervertebral disc is the major contributor to back/neck and radicular pain. It is characterized by an elevation in levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1 α/β, IL-6 and IL-17 secreted by the disc cells themselves; these cytokines promote matrix degradation, chemokine production and changes in cell phenotype. The resulting imbalance between catabolic and anabolic responses leads to degeneration, as well as herniation and radicular pain. Release of chemokines from degenerating discs promote infiltration and activation of T and B cells, macrophages, neutrophils, and mast cells further amplifying the inflammatory cascade. Immunocyte migration into the disc is accompanied by the appearance of microvasculature and nerve fibers arising from the dorsal root ganglion (DRG). In this inflammatory milieu, neurogenic factors in particular nerve growth factor (NGF) and brain-derive neurotrophic factor (BDNF) generated by disc and immune cells induce expression of pain associated cation channels in DRGs. Depolarization of these channels is likely to promote discogenic and radicular pain and reinforce the cytokine-mediated degenerative cascade. Taken together, the enhanced understanding of the contribution of cytokines and immune cells to catabolic and nociceptive processes provide new targets for treating symptomatic disc disease.

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“…These etiologic factors initiate the process of IDD mediated by the aberrant production of pro-inflammatory cytokines secreted by NP cells, annulus fibrosus (AF) cells, and infiltrated immune cells [44,45,46]. Pro-inflammatory mediators, including TNF-α, IL-1α, IL-1β, IL-6, IL-17, and various chemokines [47,48,49,50,51,52], induce autophagy, senescence or apoptosis of IVD cells [37,53,54,55,56,57,58]; decreased extracellular matrix (ECM) production [59,60]; and increased production of ECM degradative enzymes [61,62].…”

Section: The Pathogenesis Of Iddmentioning

confidence: 99%

Growth and Differentiation Factor-5 Contributes to the Structural and Functional Maintenance of the Intervertebral Disc

Feng

Liu

Yang

et al. 2015

Cell Physiol Biochem

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Intervertebral disc degeneration (IDD) is a widely recognized contributor to low back pain (LBP). The Prevention or reversal of IDD is a potential treatment for LBP. Unfortunately, current treatments for IDD are aimed at relieving symptoms rather than regenerating disc structure or function. Recently, the injection of growth factors and mesenchymal stem cell (MSC) transplantation have been shown to be promising biological therapies for IDD. Growth factors stimulate the proliferation of and matrix synthesis by intervertebral disc (IVD) cells, leading to the regeneration of degenerative discs. Growth factors, hypoxia and co-culture with nucleus pulposus (NP) cells induce MSCs to differentiate toward an NP-like phenotype, which can increase the number of functional cells in the IVD or enhance the function of endogenous disc cells to facilitate IVD regeneration. Therefore, the emerging roles of growth factors in IVD regeneration have piqued the interest of researchers. Growth factors including transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), insulin-like growth factor-1 (IGF-1) and growth and differentiation factor-5 (GDF-5), among others, have been demonstrated to enhance anabolism in IVD cells and to induce NP-like differentiation of MSCs. However, the injection of TGF, IGF and FGF into human IVDs may induce unwanted blood vessel ingrowth, which accelerates the process of IDD, the injection of GDF-5 may not have the same effect. This finding suggests that GDF-5 is a preferable growth factor for use in IDD treatment compared with TGF, IGF and FGF. The GDF-5 gene is one of the few growth factor genes that have been found to be associated with IDD thus far; moreover, the GDF-5 gene defects lead to collagen and proteoglycan abnormalities in discs in mice, suggesting that GDF-5 contributes to the structural and functional maintenance of the IVD. This review is focused on the functions of GDF-5 in the IVD and on the association between GDF-5 and a genetic predisposition to IDD. The effects of GDF-5 on IVD regeneration and on MSC differentiation are also discussed. GDF-5 plays a crucial role in the pathogenesis of IDD and is a promising therapeutic agent for IDD. Additionally, stem cell transplantation has been shown to be a promising biological therapy for IDD.

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Fas ligand plays an important role for the production of pro‐inflammatory cytokines in intervertebral disc nucleus pulposus cells

Cited by 57 publications

References 23 publications

Pathobiology of Modic changes

Pathobiology of Modic changes

Role of cytokines in intervertebral disc degeneration: pain and disc content

Growth and Differentiation Factor-5 Contributes to the Structural and Functional Maintenance of the Intervertebral Disc

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