Stimulation of Gene Expression and Loss of Anular Architecture Caused by Experimental Disc Degeneration–An In Vivo Animal Study

Guehring, Thorsten; Omlor, Georg; Lorenz, Helga; Bertram, Helge; Steck, Eric; Richter, Wiltrud; Carstens, C.; Kroeber, Markus

doi:10.1097/01.brs.0000186591.17114.e9

Cited by 51 publications

(49 citation statements)

References 36 publications

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“…LeMaitre et al found that, unlike MMP-1 which seem to be constitutively expressed in adults, the MMP-13 gene is exclusively transcribed in aging and degenerating discs [34]. These data were confirmed by Guehring et al who have shown in an experimental rabbit model that compression-induced disc degeneration is accompanied by an up-regulation of both collagenase genes [18].…”

Section: Discussionsupporting

confidence: 76%

Vertebral endplate trauma induces disc cell apoptosis and promotes organ degeneration in vitro

et al. 2007

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There is a major controversy whether spinal trauma with vertebral endplate fractures can result in posttraumatic disc degeneration. Intervertebral discs, which are adjacent to burst endplates, are frequently removed and an intercorporal spondylodesis is performed. In any case, the biological effects within the discs following endplate factures are poorly elucidated to date. The aim of our investigations was therefore to establish a novel disc/endplate trauma culture model to reproducibly induce endplate fractures and investigate concurrent disc changes in vitro. This model is based on a full-organ disc/endplate culture system, which has been validated by the authors before. Intervertebral disc/endplate specimens were isolated from Burgundy rabbits and cultured in standard media (DMEM/ F12, 10%FCS). Burst endplate fractures were induced in half of the specimens with a custom-made fracture device and subsequently cultured for 9 days. The biological effects such as necrotic or apoptotic cell death and the expression of pro-apoptotic genes and other genes involved in organ degeneration, e.g. matrix metalloproteinases (MMPs) were analyzed. Cell damage was assessed by quantification of the lactate dehydrogenase (LDH) activity in the supernatant. The expression of genes involved in the cellular apoptotic pathway (caspase 3) and the pro-apoptotic proteins FasL and TNF-a were monitored. The results demonstrate that LDH levels increased significantly post trauma compared to the control and remained elevated for 3 days. Furthermore, a constant up-regulation of the caspase 3 gene in both disc compartments was present. The pro-apoptotic proteins FasL and TNF-a were up regulated predominantly in the nucleus whereas the MMP-1 and -13 transcripts (collagenases) were increased in both disc structures. From this study we can conclude that endplate burst fractures result in both necrotic and apoptotic cell death in nucleus and annulus tissue. Moreover, FasL and TNF-a expression by nucleus cells may lead to continued apoptosis induced by Fas-and TNF-a receptor bearing cells. In addition TNF-a over-expression has potentially deleterious effects on disc metabolism such as overexpression of matrix proteinases. Taken together, the short term biological response of the disc following endplate fracture exhibits characteristics, which may initiate the degeneration of the organ.

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Section: Discussionsupporting

confidence: 76%

Vertebral endplate trauma induces disc cell apoptosis and promotes organ degeneration in vitro

et al. 2007

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“…Guehring and collaborators (39) have also shown a significant up-regulation of COL1A2 in compressed discs in an animal model. However, to explain differences in gene associations between the specific disc regions, we must also consider that at different stages of degeneration, different genes may be important and that the influence of different environmental factors and other genes (e.g., vertebral anthropometrics) can vary between discs.…”

Section: Discussionmentioning

confidence: 98%

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

Videman

Saarela

Kaprio

et al. 2009

Arthritis & Rheumatism

125

104

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Objective. To examine the allelic diversity of structural, inflammatory, and matrix-modifying gene candidates and their association with disc degeneration.Methods. Subjects were 588 men ages 35-70 years. We investigated associations of single-nucleotide polymorphisms in AGC1 and in 12 collagen, 8 interleukin, and 4 matrix metalloproteinase genes with quantitative magnetic resonance imaging measurements of disc desiccation and disc bulging and height narrowing scores, after controlling for age and suspected risk factors. Analyses were performed using QTDT software. P values were derived from 1,000 permutations, and empirical P values for global significance also were applied.Results. Twelve of the 99 variants in 25 selected candidate genes provided evidence of association (P < 0.05) with disc signal intensity in the upper and/or lower lumbar regions. Allelic variants of AGC1 (rs1042631; P ‫؍‬ 0.001), COL1A1 (rs2075555; P ‫؍‬ 0.005), COL9A1 (rs696990; P ‫؍‬ 0.00008), and COL11A2 (rs2076311; P ‫؍‬ 0.018) genes provided the most significant evidence of association with disc signal intensity. The same variants of AGC1 (P ‫؍‬ 0.010) and COL9A1 (P ‫؍‬ 0.014), as well as variants in the COL11A1 gene (rs1463035 [P ‫؍‬ 0.004]; rs1337185 [P ‫؍‬ 0.015]) were also associated with disc bulging, as was AGC1 with disc height narrowing (rs1516797; P ‫؍‬ 0.005). In addition, 4 allelic variants in the immunologic candidate genes (rs2071375 in IL1A [P ‫؍‬ 0.027]; rs1420100 in IL18RAP [P ‫؍‬ 0.005]) were associated with disc signal intensity.Conclusion. Genetic variants account for interindividual differences in disc matrix synthesis and degradation. The accuracy of the quantitative disc signal intensity measurements we used likely enhanced our ability to observe these associations. Our findings shed light on possible mechanisms of degeneration and support the view that disc degeneration is a polygenetic condition.Intervertebral disc degeneration is a suspected cause of common back pain (1), but both the etiology and pathogenesis of disc degeneration are poorly understood (2). A 1992 review of relevant scientific literature identified physical demands of occupational and leisure activities as primary risk factors, while the role of genetics was uncertain (3). However, results from later twin studies suggested that heredity plays a major role, accounting for an estimated 34-74% of variance in disc degeneration (4,5).

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“…In degenerative disc models, the decreased expression of the BMP-2 gene may represent a failed reparative response to injury (20,21). In an external-compression degenerative disc model, immunohistochemical evaluation of the compressed discs demonstrated a loss of the annular architecture and a significant reduction in the number of BMP-2-positive cells, whereas gene expression analysis showed a significant upregulation of BMP-2 (22). In a rabbit annular stab-injury model, there was a relative decrease in BMP-2 mRNA levels, followed by a consequent increase close to the preoperative levels (20).…”

Section: Discussionmentioning

confidence: 98%

Efficacy of intradiscal hepatocyte growth factor injection for the treatment of intervertebral disc degeneration

Zou

Jiang

et al. 2013

Molecular Medicine Reports

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Abstract.A poor nutritional supply to the cells of the avascular intervertebral discs, caused by dehydration of the extracellular matrix, is a major cause of intervertebral disc degeneration (IDD). Since hepatocyte growth factor (HGF) has been shown to exert antifibrotic effects, we hypothesized that HGF treatment may be capable of retarding IDD. The present study aimed to evaluate the efficacy of HGF treatment in retarding IDD in a rat tail model of disc degeneration. The disc degeneration models were induced by needle puncture of the rat tail discs. Four weeks following needle puncture, a triblock poly(lactide-co-glycolide)-poly(ethyleneglycol)-poly(lactide-co-glycolide; PLGA-PEG-PLGA) polymer gel loaded with HGF or the gel alone was injected into rat tail discs. The efficacy of HGF in retarding IDD was assessed by magnetic resonance imaging (MRI), histological and immunohistochemical evaluation of the type I collagen, type II collagen and bone morphogenetic protein-2 (BMP-2) expression levels. Following injection of the HGF-loaded gel into the nucleus pulposus (NP), a significant trend towards an increase in T2 signal intensity (P=0.028), type II collagen staining in the NP and the number of BMP-2-positive cells in the annulus fibrosus was observed. In addition, the results demonstrated a significant trend towards a decrease in the histological score (P=0.025) and type I collagen staining in the NP compared with segments treated with the gel alone, following the induction of disc degeneration by stab injury. Following treatment with HGF, a tendency for the level of disc height to be maintained was also observed (no statistical significance). By MRI, histological and immunohistochemical evaluation, the present study demonstrated that HGF-loaded PLGA-PEG-PLGA gel was able to retard disc degeneration when injected into the degenerative discs of rat tail models.

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Stimulation of Gene Expression and Loss of Anular Architecture Caused by Experimental Disc Degeneration–An In Vivo Animal Study

Abstract: Experimental moderate disc degeneration is characterized by a loss of BMP-2/4 and COL2 positive cells, although gene expression of disc constituents, catabolic enzymes, and growth factors is stimulated to reestablish disc integrity.

Cited by 51 publications

References 36 publications

Vertebral endplate trauma induces disc cell apoptosis and promotes organ degeneration in vitro

Vertebral endplate trauma induces disc cell apoptosis and promotes organ degeneration in vitro

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

Efficacy of intradiscal hepatocyte growth factor injection for the treatment of intervertebral disc degeneration

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