Comparative Gene Expression Profiling of Normal and Degenerative Discs

Anderson, D. Greg; Izzo, Marc W.; Hall, D.; Vaccaro, Alexander R.; Hilibrand, Alan S.; Arnold, William W.; Tuan, Rocky S.; Albert, Todd J.

doi:10.1097/00007632-200206150-00009

Cited by 126 publications

(97 citation statements)

References 24 publications

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“…In order to overcome these drawbacks, we designed this study that uses a combination of morphology and quantitative analytical procedures. Since tissue samples for both analyses should be small to avoid tissue bias due to substantial tissue heterogeneity [1], we chose the quantitative RT-PCR technique.…”

Section: Discussionmentioning

confidence: 99%

“…Up to now, quantitative PCR has mainly been applied to experimental settings, such as animal models of disc degeneration [1,10,17,28,33,37]. In summary, these models provide clear evidence that either acute or more protracted lesion of annular and/or nuclear disc tissue leads to an initial up-regulation of major MMPs, such as MMP-3 [18], MMP-13 [17,28] and MMPs-1 and -9 [1].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that particularly MMP-1, -2 and -3 are increasingly expressed in degenerated disc tissue samples as evidenced by biochemistry, immunohistochemistry (protein), in situ hybridization (mRNA expression) and enhanced enzymatic, gelatinolytic activity (in situ zymography) [1,8,9,15,18,22,29,31,33,36]. Despite these preliminary data, it remains unclear which member(s) of the MMP family are mainly responsible for the matrix disruption and decomposition.…”

Section: Introductionmentioning

confidence: 99%

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Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration

et al. 2009

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The disruption of the extracellular disc matrix is a major hallmark of disc degeneration. This has previously been shown to be associated with an up-regulation of major matrix metalloproteinase (MMP) expression and activity. However, until now hardly any data are available for MMP/ TIMP regulation and thereby no concept exists as to which MMP/TIMP plays a major role in disc degeneration. The objective of this study was, therefore, to identify and quantify the putative up-regulation of MMPs/TIMPs on the mRNA and protein level and their activity in disc material in relation to clinical data and histological evidence for disc degeneration. A quantitative molecular analysis of the mRNA expression levels for the MMPs (MMPs-1, -2, -3, -7, -8, -9, -13) and the MMP inhibitors (TIMPs-1 and -2) was performed on 37 disc specimens obtained from symptomatic disc herniation or degeneration. In addition, disc specimens from patients without disc degeneration/herniation (=con-trols) were analyzed. Expression of MMPs-1, -2, -3, -7, -8, -9, -13 and TIMPs-1, -2 was analyzed using quantitative RT-PCR, normalized to the expression level of a house keeping gene (GAPDH). Gene expression patterns were correlated with MMP activity (in situ zymography), protein expression patterns (immunohistochemistry), degeneration score (routine histology) and clinical data. MMP-3 mRNA levels were consistently and substantially up-regulated in samples with histological evidence for disc degeneration. A similar but less pronounced up-regulation was observed for MMP-8. This up-regulation was paralleled by the expression of TIMP-1 and to a lesser extent TIMP-2. In general, these findings could be confirmed with regard to protein expression and enzyme activity. This study provides data on the gene and protein level, which highlights the key role of MMP-3 in the degenerative cascade leading to symptomatic disc degeneration and herniation. Control of the proteolytic activity of MMP-3 may, therefore, come into the focus when aiming to develop new treatment options for early disc degeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration

et al. 2009

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“…Two independent investigations on rabbit disc stab models also demonstrated a degenerative matrix gene expression in the postinterventional course. 53,54 Murakami et al 55 demonstrated that the relative gene expression of type I collagen was increased and of type II collagen and aggrecan diminished in aging rabbit discs. Moreover, in our model organ swelling was inhibited by diurnal osmotic loading (not shown).…”

Section: Discussionmentioning

confidence: 99%

Influence of diurnal hyperosmotic loading on the metabolism and matrix gene expression of a whole‐organ intervertebral disc model

Haschtmann

Stoyanov

Ferguson

2006

Journal Orthopaedic Research

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It is generally agreed that the mechanical environment of intervertebral disc cells plays an important role in maintaining a balanced matrix metabolism. The precise mechanism by which the signals are transduced into the cells is poorly understood. Osmotic changes in the extracellular matrix (ECM) are thought to be involved. Current in-vitro studies on this topic are mostly short-term and show conflicting data on the reaction of disc cells subjected to osmotic changes which is partially due to the heterogenous and often substantially-reduced culture systems. The aim of the study was therefore to investigate the effects of cyclic osmotic loading for 4 weeks on metabolism and matrix gene expression in a full-organ intervertebral disc culture system. Intervertebral disc/endplate units were isolated from New Zealand White Rabbits and cultured either in iso-osmotic media (335 mosmol/kg) or were diurnally exposed for 8 hours to hyper-osmotic conditions (485 mosmol/kg). Cell viability, metabolic activity, matrix composition and matrix gene expression profile (collagen types I/II and aggrecan) were monitored using Live/Dead cell viability assay, tetrazolium reduction test (WST 8), proteoglycan and DNA quantification assays and quantitative PCR. The results show that diurnal osmotic stimulation did not have significant effects on proteoglycan content, cellularity and disc cell viability after 28 days in culture. However, hyperosmolarity caused increased cell death in the early culture phase and counteracted upregulation of type I collagen gene expression in nucleus and annulus cells. Moreover, the initially decreased cellular dehydrogenase activity recovered with osmotic stimulation after 4 weeks and aggrecan gene down-regulation was delayed, although the latter was not significant according to our statistical criteria. In contrast, collagen type II did not respond to the osmotic changes and was downregulated in both groups. In conclusion, diurnal hyper-osmotic stimulation of a whole-organ disc/ endplate culture partially inhibits a matrix gene expression profile as encountered in degenerative disc disease and counteracts cellular metabolic hypo-activity. ß

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“…For example, as matrix equilibrium shifts to a pro-catabolic state with advancing degeneration in articular cartilage, collagenasemediated degradation of type II collagen becomes more prominent (Hollander et al, 1994;Billinghurst et al, 1997). Among the collagenases, collagenase-3 (MMP-13) has been found to play a significant role in the development of both OA and DDD (Billinghurst et al, 1997;Fernandes et al, 1998;Anderson et al, 2002;Le Maitre et al, 2004). In articular cartilage, MMP-13 is almost exclusively produced by chondrocytes and has a dual role in ECM *Correspondence to : Hee-Jeong Im, Ph.D., Cohn Research BD 516, 1735 W. Harrison, Chicago, IL 60612, 312-942-3091 (Tel), 312-942-3053 (fax), Email : Hee-Jeong_Sampen@rush.edu.destruction as it degrades bothaggrecan and collagen type II (Fosang et al, 1996;Mitchell et al, 1996;Reboul et al, 1996;Fernandes et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

Ellman

Muddasani

et al. 2008

Gene

152

131

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Comparative Gene Expression Profiling of Normal and Degenerative Discs

Cited by 126 publications

References 24 publications

Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration

Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration

Influence of diurnal hyperosmotic loading on the metabolism and matrix gene expression of a whole‐organ intervertebral disc model

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

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