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

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 (=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.

Transcript levels of major MMPs and ADAMTS-4 in relation to the clinicopathological profile of patients with lumbar disc herniation

“…Nevertheless, limited evidence exists regarding the molecular profile of MMPs in ID herniation. In a recent study, Bachmeier et al [3] examined the transcript levels of several MMPs in a group of lumbar-degenerated and -herniated discs. The authors found a substantial up-regulation of MMP-3 and -8 mRNA levels.…”

Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods

“…Several factors, such as biological, mechanical and genetic factors, are widely considered as significant contributors to the disc degenerative process (1). For example, Bachmeier et al (13) identified that matrix metalloproteinase-3 (MMP-3), which was essential for matrix degeneration, had an essential role in lumbar disc herniation and degeneration. Additionally, Takahashi et al (14) revealed that the polymorphism 5A allele, which often occurs in the promoter region of the gene that regulates MMP-3 expression, was a possible risk factor for accelerated IDD in the elderly.…”

Chondroadherin Fragmentation Mediated by the Protease HTRA1 Distinguishes Human Intervertebral Disc Degeneration from Normal Aging

“…MMP-1, -2, -3, -7, -8, -9, and -13 along with ADAMTS-4 and -5 have been shown to be up-regulated in the IVD during degeneration and are responsible for the breakdown of important components of the extracellular matrix, including aggrecan and collagen (15,16). Furthermore, striking expression of cathepsins K, D, and L has been shown in degenerate IVD tissue (17).…”