Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration

Abstract

BACKGROUND CONTEXT Destruction of extracellular matrix (ECM) leads to intervertebral disc degeneration (IDD), which underlies many spine-related disorders. Matrix metalloproteinases (MMPs), and disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) are believed to be the major proteolytic enzymes responsible for ECM degradation in the intervertebral disc (IVD). PURPOSE To summarize the current literature on gene expression and regulation of MMPs, ADAMTSs, and tissue inhibitors of metalloproteinases (TIMPs) in IVD aging and IDD. METHODS A comprehensive literature review of gene expression of MMP, ADAMTS, and TIMP in human IDD and reported studies on regulatory factors controlling their expressions and activities in both human and animal model systems. RESULTS Upregulation of specific MMPs (MMP-1, -2, -3, -7, -8, -10, and -13) and ADAMTS (ADAMTS-1, -4, and -15) were reported in human degenerated IVDs. However, it is still unclear from conflicting published studies whether the expression of ADAMTS-5, the predominant aggrecanase, is increased with IDD. Tissue inhibitors of metalloproteinase-3 is downregulated, whereas TIMP-1 is upregulated in human degenerated IVDs relative to nondegenerated IVDs. Numerous studies indicate that the expression levels of MMP and ADAMTS are modulated by a combination of many factors, including mechanical, inflammatory, and oxidative stress, some of which are mediated in part through the p38 mitogen-activated protein kinase pathway. Genetic predisposition also plays an important role in determining gene expression of MMP-1, -2, -3, and -9. CONCLUSIONS Upregulation of MMP and ADAMTS expression and enzymatic activity is implicated in disc ECM destruction, leading to the development of IDD. Future IDD therapeutics depends on identifying specific MMPs and ADAMTSs whose dysregulation result in pathological proteolysis of disc ECM.

The Significance of Matrix Metalloproteinases in Oral Diseases

“…− on the level of altering gene expression in patients with a genetic predispositions [26]; − on the level of transcription by cytokines (IL-1, TNF), hormones (parathormone, PTH) and bacteria products (LPS); − on the level of enzyme sequestration to intracellular bubbles; − on the level proenzyme activation (metal ions, oxidative stress, detergents, other proteolytic enzymem, plasmin); − on the level of substrate specificity; − through the pH of the environment; − through tissue inhibitors of metalloproteinases (TIMPs) and serine protease inhibitors (serpins) [27].…”

Creation of an injectable in situ gelling native extracellular matrix for nucleus pulposus tissue engineering

“…Tissue engineering approaches often combine growth factors and cells to attempt to repair the nucleus pulposus; however, in the harsh catabolic environment of the degenerating disc, growth factors and cells cannot survive [15][16][17][18][19][20]. The addition of a biomaterial carrier has the potential to increase cell viability and enable long-term growth factor delivery.…”

Bioinformatics analysis of molecular mechanisms involved in intervertebral disc degeneration induced by TNF-α and IL-1β

“…However, the anulus fibrosus becomes weaker with increasing age (3), resulting in intervertebral disc degeneration (IDD). Beyond age 40, >60% of individuals show symptoms of IDD; furthermore, IDD is the most common cause of disability among workers aged 18-64 years (4). IDD is characterized by decreases in intervertebral disc function and height due to cell loss through apoptosis, increased breakdown of matrix or altered matrix synthesis, with the underlying pathological processes being complex (5)(6)(7).…”

“…Vo et al (4) reported that IDD was a consequence of increased catabolism of the extracellular matrix (ECM), since the proteolytic degradation of ECM macromolecules led to marked structural changes of the intervertebral disc. These catabolic processes are mediated by a number of cytokines in the nucleus pulposus, among which interleukin (IL)-1β and tumor necrosis factor (TNF)-α have been suggested to have crucial roles in the development of IDD.…”