Matrix Metalloproteinase Expression Levels Suggest Distinct Enzyme Roles During Lumbar Disc Herniation and Degeneration

Overview

Journal Eur Spine J

Specialty Orthopedics

Date 2009 May 26

PMID 19466462

Citations 85

Authors

Beatrice E Bachmeier

Andreas Nerlich

Norbert Mittermaier

Christoph Weiler

Christianto Lumenta

Karin Wuertz

Norbert Boos

Affiliations

Soon will be listed here.

Abstract

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 (=controls) 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.

Citing Articles

MARCHF8-mediated ubiquitination via TGFBI regulates NF-κB dependent inflammatory responses and ECM degradation in intervertebral disc degeneration.

Zhang X, Li G, Tan F, Yu T, Xu C, Li K PLoS One. 2025; 20(1):e0314021.

PMID: 39752341 PMC: 11698339. DOI: 10.1371/journal.pone.0314021.

In vitro and ex vivo screening of microRNA combinations with enhanced cell penetrating peptides to stimulate intervertebral disc regeneration.

Ni Neill T, Barcellona M, Wilson N, OBrien F, Dixon J, Curtin C JOR Spine. 2024; 7(4):e1366.

PMID: 39726900 PMC: 11669629. DOI: 10.1002/jsp2.1366.

Title Changes in Plasma Levels of Selected Matrix Metalloproteinases (MMPs) Enzymes in Patients with Osgood-Schlatter Disease (OSD).

Kulesza M, Guszczyn T, Kicman A, Lawicki S J Clin Med. 2024; 13(19).

PMID: 39407715 PMC: 11477660. DOI: 10.3390/jcm13195655.

The Expression of Toll-like Receptors in Cartilage Endplate Cells: A Role of Toll-like Receptor 2 in Pro-Inflammatory and Pro-Catabolic Gene Expression.

Mengis T, Bernhard L, Nuesch A, Heggli I, Herger N, Devan J Cells. 2024; 13(17.

PMID: 39272974 PMC: 11394474. DOI: 10.3390/cells13171402.

Getting to the Core: Exploring the Embryonic Development from Notochord to Nucleus Pulposus.

Ambrosio L, Schol J, Ruiz-Fernandez C, Tamagawa S, Joyce K, Nomura A J Dev Biol. 2024; 12(3).

PMID: 39051200 PMC: 11270426. DOI: 10.3390/jdb12030018.

References

Cs-Szabo G, Turumella V, Masuda K, Thonar E, An H . Changes in mRNA and protein levels of proteoglycans of the anulus fibrosus and nucleus pulposus during intervertebral disc degeneration. Spine (Phila Pa 1976). 2002; 27(20):2212-9. DOI: 10.1097/00007632-200210150-00006. View

Haro H, Crawford H, Fingleton B, MacDougall J, Shinomiya K, Spengler D . Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc resorption. J Clin Invest. 2000; 105(2):133-41. PMC: 377425. DOI: 10.1172/JCI7090. View

Crean J, Roberts S, Jaffray D, Eisenstein S, Duance V . Matrix metalloproteinases in the human intervertebral disc: role in disc degeneration and scoliosis. Spine (Phila Pa 1976). 1998; 22(24):2877-84. DOI: 10.1097/00007632-199712150-00010. View

Sobajima S, Shimer A, Chadderdon R, Kompel J, Kim J, Gilbertson L . Quantitative analysis of gene expression in a rabbit model of intervertebral disc degeneration by real-time polymerase chain reaction. Spine J. 2005; 5(1):14-23. DOI: 10.1016/j.spinee.2004.05.251. View

Matsui Y, Maeda M, Nakagami W, Iwata H . The involvement of matrix metalloproteinases and inflammation in lumbar disc herniation. Spine (Phila Pa 1976). 1998; 23(8):863-8; discussion 868-9. DOI: 10.1097/00007632-199804150-00005. View

Gruber H, Ingram J, Hanley Jr E . Immunolocalization of MMP-19 in the human intervertebral disc: implications for disc aging and degeneration. Biotech Histochem. 2005; 80(3-4):157-62. DOI: 10.1080/10520290500387607. View

MacLean J, Lee C, Alini M, Iatridis J . The effects of short-term load duration on anabolic and catabolic gene expression in the rat tail intervertebral disc. J Orthop Res. 2005; 23(5):1120-7. DOI: 10.1016/j.orthres.2005.01.020. View

Rannou F, Lee T, Zhou R, Chin J, Lotz J, Mayoux-Benhamou M . Intervertebral disc degeneration: the role of the mitochondrial pathway in annulus fibrosus cell apoptosis induced by overload. Am J Pathol. 2004; 164(3):915-24. PMC: 1613264. DOI: 10.1016/S0002-9440(10)63179-3. View

Haro H, Crawford H, Fingleton B, Shinomiya K, Spengler D, Matrisian L . Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc resorption. J Clin Invest. 2000; 105(2):143-50. PMC: 377426. DOI: 10.1172/JCI7091. View

10.

Nemoto O, Yamagishi M, Yamada H, Kikuchi T, Takaishi H . Matrix metalloproteinase-3 production by human degenerated intervertebral disc. J Spinal Disord. 1998; 10(6):493-8. View

11.

Visse R, Nagase H . Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003; 92(8):827-39. DOI: 10.1161/01.RES.0000070112.80711.3D. View

12.

Nakada M, Nakamura H, Ikeda E, Fujimoto N, Yamashita J, Sato H . Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. Am J Pathol. 1999; 154(2):417-28. PMC: 1850004. DOI: 10.1016/S0002-9440(10)65288-1. View

13.

Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt K, Nerlich A . Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science. Spine (Phila Pa 1976). 2002; 27(23):2631-44. DOI: 10.1097/00007632-200212010-00002. View

14.

Kang J, Stefanovic-Racic M, McIntyre L, Georgescu H, Evans C . Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine (Phila Pa 1976). 1997; 22(10):1065-73. DOI: 10.1097/00007632-199705150-00003. View

15.

Haro H, Komori H, Kato T, Hara Y, Tagawa M, Shinomiya K . Experimental studies on the effects of recombinant human matrix metalloproteinases on herniated disc tissues--how to facilitate the natural resorption process of herniated discs. J Orthop Res. 2005; 23(2):412-9. DOI: 10.1016/j.orthres.2004.08.020. View

16.

Pockert A, Richardson S, Le Maitre C, Lyon M, Deakin J, Buttle D . Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration. Arthritis Rheum. 2009; 60(2):482-91. DOI: 10.1002/art.24291. View

17.

Bachmeier B, Albini A, Vene R, Benelli R, Noonan D, Weigert C . Cell density-dependent regulation of matrix metalloproteinase and TIMP expression in differently tumorigenic breast cancer cell lines. Exp Cell Res. 2005; 305(1):83-98. DOI: 10.1016/j.yexcr.2004.12.019. View

18.

Anderson D, Izzo M, Hall D, Vaccaro A, Hilibrand A, Arnold W . Comparative gene expression profiling of normal and degenerative discs: analysis of a rabbit annular laceration model. Spine (Phila Pa 1976). 2002; 27(12):1291-6. DOI: 10.1097/00007632-200206150-00009. View

19.

Nerlich A, Bachmeier B, Boos N . Expression of fibronectin and TGF-beta1 mRNA and protein suggest altered regulation of extracellular matrix in degenerated disc tissue. Eur Spine J. 2004; 14(1):17-26. PMC: 3476681. DOI: 10.1007/s00586-004-0745-x. View

20.

Woessner Jr J . Activation of cartilage stromelysin-1 at acid pH and its relation to enzyme pH optimum and osteoarthritis. Agents Actions. 1993; 40(3-4):228-31. DOI: 10.1007/BF01984067. View