Matrix synthesis and degradation in human intervertebral disc degeneration

Abstract

Degeneration of the intervertebral disc has been implicated in chronic low back pain. Type II collagen and proteoglycan (predominantly aggrecan) content is crucial to proper disc function, particularly in the nucleus pulposus. In degeneration, synthesis of matrix molecules changes, leading to an increase in the synthesis of collagens type I and III and a decreased production of aggrecan. Linked to this is an increased expression of matrix-degrading molecules including MMPs (matrix metalloproteinases) and the aggrecanases, ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) 1, 4, 5, 9 and 15, all of which are produced by native disc cells. Importantly, we have found that there is a net increase in these molecules, over their natural inhibitors [TIMP-1 (tissue inhibitor of metalloproteinases-1), 2 and 3], suggesting a deregulation of the normal homoeostatic mechanism. Growth factors and cytokines [particularly TNFalpha (tumour necrosis factor alpha) and IL-1 (interleukin 1)] have been implicated in the regulation of this catabolic process. Our work has shown that in degenerate discs there is an increase in IL-1, but no corresponding increase in the inhibitor IL-1 receptor antagonist. Furthermore, treatment of human disc cells with IL-1 leads to a decrease in matrix gene expression and increased MMP and ADAMTS expression. Inhibition of IL-1 would therefore be an important therapeutic target for preventing/reversing disc degeneration.

Nerve growth factor increases MMP9 activity in annulus fibrosus cells by upregulating lipocalin 2 expression

“…Overexpression of MMPs is clearly associated with both osteoarthritis and IVD degeneration [12]. In the current study, our microarray results indicated that NGF increases expression of a number of MMPs such as MMP3 and MMP13 consistent with previous investigations that have shown similar activity of NGF in other tissues and cell systems, including smooth muscle cells and pancreatic cancer cells [13,24].…”

“…Matrix degradation as a result of over production of matrix metalloproteinases (MMPs) is a major component of the pathological processes that lead to IVD degeneration [12] and NGF has been shown to increase MMP expression in a number of tissues and cell systems [13]. Furthermore, NGF has been shown to induce neoangiogenesis in a range of normal and pathological conditions [14].…”

The elastic fibre network of the human lumbar anulus fibrosus: architecture, mechanical function and potential role in the progression of intervertebral disc degeneration

“…As discussed previously, elastic fibres contain molecules other than elastin, in particular fibrillins, which are the principal components of elastic microfibrils. Fibrillins are degraded by several members of the matrix metalloproteinase family [4]; in particular, these include MMPs-2, -3, and -13, which demonstrate increased presence in degenerate discs [36].…”

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

“…It is characterized by structural failure and loss of IVD height due to proteolytic degradation of the extracellular matrix (1). Lower back pain in adult individuals is commonly associated with IVD degeneration (2).…”