Sequential dynamics of inflammatory cytokine, angiogenesis inducing factor and matrix degrading enzymes during spontaneous resorption of the Herniated disc

Abstract

Intervertebral disc herniation (HD) is one of the most common orthopaedic conditions. MRI analysis of H D has revealed a spontaneous resorption mechanism related with neo-vascularization. It appears that the interaction of activated macrophages with disc tissues leads to the generation of inflammatory cytokines. Moreover, inflammatory cytokines such as tumor necrosis factor-a (TNF-a) is required for the induction of angiogenesis inducing factors such as vascular endothelial growth factor (VEGF) or matrix degrading enzymes such as MMP-3, MMP-7 and plasmin. We hypothesized that these molecules play a crucial role during spontaneous H D resorption. In this study, we have examined the sequential expression of these molecules using a co-culture system which is composed of the interaction of activated macrophages and disc tissues as a model of the acute response of inflammation occurred in HD. We have also considered the mechanism of activating latent MMPs during H D resorption process. Current our results indicate that upregulation of both TNF-cl mRNA and protein expressions occur first in the inflammation induced by HD. VEGF upregulation follows the increased level of TNF-a expression. Both plasmin and MMP-3 are upregulated at later time points. We also demonstrate that both TNF-a and VEGF induce upregulated expression of urokinase-type plasminogen activator (u-PA). Our previous work has demonstrated that TNF-(r could upregulate the expression of VEGF, MMP-3 and MMP-7 in the co-culture system. It has been reported that plasmin could affect to activate latent MMPs. Based on these findings, we suggest that TNF-a acts as the initiator of inflammation following contact between macrophages and disc chondrocytes and that plasmin and u-PA play a crucial role in activation of MMPs. We propose a spontaneous H D resorption cascade. Further understanding of the resorption process may provide future novel therapies for HD.

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

“…MMP production in ID tissue is mediated by cytokines, growth factors and inflammatory mediators. The role of interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) has been documented in vitro [15]. Growth factors are known to affect the process of ID degeneration by inducing neovascularization and regulating MMP expression levels [23].…”

“…Contact between the herniated fragment of the ID and the epidural space was thought to trigger an autoimmune response with inflammatory cell infiltration and in situ neovascularization, leading to the progressive resorption of the herniated fragment and regression of symptoms. Mounting evidence has shown that growth factors, matrix metalloproteinases (MMPs) and inflammatory mediators, such as cytokines, play a key role in ID homeostasis and pathology [9,15]. However, the role of such molecules in the pathogenesis of ID herniation as well as in the spontaneous regression of herniated disc fragments remains only partially elucidated.…”

Vertebral endplate trauma induces disc cell apoptosis and promotes organ degeneration in vitro

“…Numerous pathobiological changes and inflammatory cascades, such as the induction of programmed cell death (apoptosis), chemotactic recruitment of leukocytes and the activation of matrix-degrading metalloproteinases (MMPs) can be expected [4,27,51].…”

Association between VEGF and eNOS gene polymorphisms and lumbar disc degeneration in a young Korean population

“…Thus, we can infer that increased VEGF expression may aggravate IVD degeneration through the progress of atherosclerosis or calcification leading to occlusion of endplate openings, and further exacerbate low back pain by inducing nociceptive nerve ingrowth into degenerated disc. Conversely, others suggest that the VEGF is protective against IVD degeneration via the neovascularization of the degenerative disc (Haro et al, 2002;Kato et al, 2004;Walsh, 2004). Angiogenesis may be regarded as a part of the repair response (Haro et al, 2002).…”