Dataset Information

Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs.

ABSTRACT: INTRODUCTION: The regulation and elevation in expression of the catabolic matrix metalloproteinases (MMPs) is of high importance in the human intervertebral disc since upregulation of these matrix-degrading enzymes results in matrix destruction associated with disc degeneration. MMP28 (epilysin) is a newly discovered MMP believed to play a role in matrix composition and turnover in skin. It is present in basal keratinocytes where its expression is upregulated with wound repair, and in cartilage and synovium where it is upregulated in osteoarthritis. Recent work has shown that mechanical compression can act to modulate expression of MMP28. The expression of MMP28 is unexplored in the intervertebral disc. METHODS: Following approval by our human subjects institutional review board, we employed microarray analyses to evaluate in vivo expression of MMP28 and the MMP28 precursor in human disc tissue, and utilized immunohistochemistry to determine cellular and extracellular matrix localization of MMP28 in 35 human disc tissue specimens. The percentage of cells positive for MMP28 immunocytochemical localization was also determined. RESULTS: The present work documents the expression and presence of MMP28 in cells and extracellular matrix (ECM) of the human intervertebral disc. Gene expression levels in human disc tissue were detectable for both MMP28 and the MMP28 precursor. MMP28 cytoplasmic localization was present in cells of the outer annulus; it was also present in some, but not all, cells of the inner annulus and nucleus. MMP28 was not found in the ECM of healthier Grade I to II discs, but was identified in the ECM of 61% of the more degenerated Grade III to V discs (P = 0.0018). There was a significant difference in cellular MMP28 distribution in the disc (P = 0.008): the outer annulus showed the largest percentage of cells positive for MMP28 immunolocalization, followed by the inner annulus and then the nucleus. Herniated discs showed a significantly greater proportion of MMP28-positive cells compared with nonherniated discs (P = 0.034). CONCLUSIONS: Findings presented here show the first documentation of intervertebral disc expression and production of MMP28. MMP28 was found in both disc cell cytoplasm and in the ECM of more degenerated specimens, with greater cellular localization in the outer annulus and in herniated disc specimens. These findings are important because of the key role of MMPs in disc turnover and homeostasis, and previous indications of a role for this MMP in matrix repair and matrix turnover in other tissues. Our data, which show the presence of MMP28 in human disc tissue, suggest that MMP28 may have a potentially important role in ECM modulation in the healthy and degenerating disc.

SUBMITTER: Gruber HE

PROVIDER: S-EPMC3003526 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs.

Gruber Helen E HE Ingram Jane A JA Hoelscher Gretchen L GL Zinchenko Natalia N Norton H James HJ Hanley Edward N EN

Arthritis research & therapy 20091209 6

<h4>Introduction</h4>The regulation and elevation in expression of the catabolic matrix metalloproteinases (MMPs) is of high importance in the human intervertebral disc since upregulation of these matrix-degrading enzymes results in matrix destruction associated with disc degeneration. MMP28 (epilysin) is a newly discovered MMP believed to play a role in matrix composition and turnover in skin. It is present in basal keratinocytes where its expression is upregulated with wound repair, and in car ...[more]

PMID: 20003223

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Project description:Regenerative therapies for intervertebral disc (IVD) injuries are currently a major challenge that is addressed in different ways by scientists working in this field. Extracellular matrix (ECM) deriving from decellularized non-autologous tissues has been established as a biomaterial with remarkable regenerative capacity and its potential as a therapeutic agent is rising. In the present study, we investigated the potential of decellularized Wharton's jelly matrix (DWJM) from human umbilical cord to act as an ECM-based scaffold for IVD cell culturing. An efficient detergent-enzymatic treatment (DET) was used to produce DWJM maintaining its native microarchitecture. Afterward, immunofluorescence, biochemical assays and electron microscopy analysis showed that DWJM was able to produce sizeable 3D cell aggregates, when combined with human mesenchymal stromal cells isolated from WJ (MSCs) and IVD cells. These latter cells are characterized by the loss of their chondrocyte-like phenotype since they have been isolated from degenerated IVD and in vitro expanded to further de-differentiate. While the effect exerted by DWJM on MSCs was essentially the induction of proliferation, conversely, on IVD cells the DWJM promoted cell differentiation toward a discogenic phenotype. Notably, for the first time, the ability of DWJM to improve the degenerated phenotype of human IVD cells was demonstrated, showing that the mere presence of the matrix maintained the viability of the cells, and positively affected the expression of critical regulators of IVD homeostasis, such as SOX2, SOX9, and TRPS1 transcription factors at specific culture time. Our data are in line with the hypothesis that the strengthening of cell properties in terms of viability and expression of specific proteins at precise times represents an important condition in the perspective of guiding the recovery of cellular functionality and triggering regenerative potential. Currently, there are no definitive surgical or pharmacological treatments for IVD degeneration (IDD) able to restore the disc structure and function. Therefore, the potential of DWJM to revert degenerated IVD cells could be exploited in the next future an ECM-based intradiscal injectable therapeutic.

Project description:Intervertebral disc (IVD) degeneration is a pathological process, which may lead to lower back pain. The present study aimed to investigate the pathogenesis of IVD degeneration. GSE42611 was downloaded from Gene Expression Omnibus, including 4 nucleus pulposus samples isolated from degenerated IVDs and 4 nucleus pulposus samples separated from normal IVDs. The differentially expressed genes (DEGs) between the degenerated and normal samples were screened using the limma package in R. Functional and pathway enrichment analyses were conducted separately for the upregulated and downregulated genes, using Database for Annotation, Visualization and Integrated Discovery software. In addition, protein‑protein interaction (PPI) networks were constructed using the Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. Finally, module analyses were conducted for the PPI networks using the MCODE plug‑in in Cytoscape. A total of 558 DEGs were identified in the degenerated nucleus pulposus cells: 253 upregulated and 305 downregulated. Pathway enrichment analysis revealed that downregulated thrombospondin 1 (THBS1) was enriched in extracellular matrix‑receptor interaction. Interleukin (IL)‑6 in the PPI network for the upregulated genes and vascular endothelial growth factor A (VEGFA) in the PPI network for the downregulated genes had higher degrees. Additionally, four modules (µM1, µM2, µM3 and µM4) were identified from the PPI network for the upregulated genes. Four modules (dM1, dM2, dM3 and dM4) were identified from the PPI network for the downregulated genes. In the dM2 module, collagen genes and integrin subunit α4 (ITGA4) may interact with each other. Additionally, functional enrichment indicated that collagen genes were enriched in extracellular matrix organization. In conclusion, IL‑6, VEGFA, THBS1, ITGA4 and collagen genes may contribute to the progression of IVD degeneration. These results suggested that the manipulation of these genes and their products may have potential as a novel therapeutic strategy for the treatment of patients with IVD.

Dataset Information

Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs.

Publications

Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs.

Similar Datasets

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