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Transgenic mice overexpressing human TNF-? experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration.

ABSTRACT: There is a well-established link between cytokine expression and the progression of intervertebral disc degeneration. Among these cytokines, interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?) are the most commonly studied. To investigate whether systemic hTNF-? overexpression affects intervertebral disc health, we studied the spine phenotype of Tg197 mice, a widely used hTNF-? transgenic line. These mice were studied at 12-16 weeks of age using comprehensive histochemical and immunohistological analysis of the spinal motion segment. Micro-CT analysis was performed to quantify vertebral trabecular bone architecture. The Tg197 mice evidenced spontaneous annular tears and herniation with increased vascularity in subchondral bone and significant immune cell infiltration. The full-thickness annular tear without nucleus pulposus (NP) extrusion resulted in neutrophil, macrophage, and mast cell infiltration into the disc, whereas the disc with full-thickness tear and pronounced NP herniation showed additional presence of CD4+ and CD8+ T cells. While the observed defects involved failure of the annular, endplate, and vertebral junction, there were no obvious alterations in the collagen or aggrecan content in the NP and annulus fibrosus or the maturity of collagen fibers in Tg197 mice. Despite elevated systemic inflammation and pronounced loss of trabecular bone in the vertebrae, intact Tg197 discs were healthy and showed an increase in NP cell number. The NP cells in intact discs preserved expression of phenotypic markers: CAIII, Glut1, and Krt19. In conclusion, elevated systemic TNF-? increases the susceptibility of mice to spontaneous disc herniation and possibly radiculopathy, without adversely affecting intact intervertebral disc health.

SUBMITTER: Gorth DJ

PROVIDER: S-EPMC6315044 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Transgenic mice overexpressing human TNF-α experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration.

Gorth Deborah J DJ Shapiro Irving M IM Risbud Makarand V MV

Cell death & disease 20181218 1

There is a well-established link between cytokine expression and the progression of intervertebral disc degeneration. Among these cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are the most commonly studied. To investigate whether systemic hTNF-α overexpression affects intervertebral disc health, we studied the spine phenotype of Tg197 mice, a widely used hTNF-α transgenic line. These mice were studied at 12-16 weeks of age using comprehensive histochemical and immunohisto ...[more]

PMID: 30584238

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Project description:Intervertebral disc herniation (IVDH) is an important pathology in humans and also in dogs. While the molecular disease mechanisms are well investigated in humans, little is known about the inflammatory mediators in naturally occurring canine IVDH. The objective of this study was to investigate whether the involved proinflammatory cytokines in human IVDH are also key cytokines in canine IVDH and thus to elucidate the suitability of the dog as a model for human trials. 59 samples from 25 dogs with surgically confirmed thoracolumbar IVDH were collected and classified in three subgroups: herniated (H), affected non-herniated (NH) disc, and adjacent non-affected (NA) disc. Discs from 11 healthy dogs acted as controls (C). Samples were analyzed for IL-1, IL-6, IL-8, and TNF-? expression (qPCR/ELISA) as well as cell infiltration and activation of the MAP kinase pathways (immunohistochemistry). Gene and protein expression of all key cytokines could be detected in IVDH affected dogs. Canine IVDH was significantly associated with a higher gene expression of IL-6 (H?>?C, NH?>?C) and TNF-? (H?>?C, NH?>?C, NA?>?C) and a significant down-regulation of IL-1? (H?<?C). Dogs with spontaneous pain had significantly higher IL-6 mRNA compared to those with pain arising only upon palpation. An inter-donor comparison (H and HN relative to NA) revealed a significant increase of IL-6 gene expression (H?>?NA, NH?>?NA). IL-8 (H?>?C, NA?>?C) and TNF-? (NH?>?C) protein levels were significantly increased in diseased dogs while inversely, IL-6 protein levels were significantly higher in patients with better clinical outcome. Aside from resident IVD cells, mostly monocytes and macrophages were found in extruded material, with concomitant activation of extracellular signal-regulated kinase p38 in the majority of samples. Dogs with spontaneous IVDH might provide a useful model for human disc diseases. Although the expression of key cytokines found in human IVDH was also demonstrated in canine tissue, the inflammatory mechanisms accompanying canine IVDH diverges partially from humans, which will require further investigations in the future. In dogs, IL-6 seems to play an important pathological role and may represent a new potential therapeutic target for canine patients.

Project description:BackgroundIntervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects.ObjectiveThis study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein.MethodsWe exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin.ResultsDigoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells.ConclusionThese findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.

Dataset Information

Transgenic mice overexpressing human TNF-? experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration.

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Transgenic mice overexpressing human TNF-α experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration.

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