Analysis of Tissue Distribution of TNF‐α, TNF‐α‐Receptors, and the Activating TNF‐α–Converting Enzyme Suggests Activation of the TNF‐α System in the Aging Intervertebral Disc

Abstract

We immunohistochemically analyzed the expression and localization of TNF-alpha, its receptors TNF-RI and -RII, and the TNF-alpha-activating enzyme TACE in human autopsy (n=63) and surgical (n=35) lumbar intervertebral disc samples. In parallel, the TNF-alpha-mRNA was quantified by reverse transcriptase-polymerase chain reaction (RT-PCR). All samples were morphometrically evaluated for the proportion of positively labeled cells in the different anatomical regions of the disc. We detected a significant and comparable expression of all four parameters beginning in young adult age (c. 18 years) and being most extensive in the nucleus pulposus. This level was slightly reduced in older age discs. The annulus fibrosus contained significantly less labeled cells. In accord, the number of TNF-alpha-transcripts was elevated in most cases with immunohistochemical TNF-alpha expression. We provide clear evidence that TNF-alpha is expressed in discs of increasing age, which correlates with histomorphological signs of disc degeneration. In consequence, TNF-alpha seems to be activated (by the converting enzyme TACE) and biologically active through its receptors in human lumbar disc tissue.

TNF-α and IL-1β Promote a Disintegrin-like and Metalloprotease with Thrombospondin Type I Motif-5-mediated Aggrecan Degradation through Syndecan-4 in Intervertebral Disc

“…In human as well as animal models of degenerative disc disease there are increased levels of inflammatory cytokine such as TNF-␣ and IL-1␤; our studies confirmed and extended these earlier findings (7,8,(23)(24)(25)(26)(27)(28). Likewise, in both mouse and human articular cartilage, cytokines and SDC4 expression is elevated during osteoarthritis (18).…”

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

“…In patients with lumbar disc herniation, more TNF-α-immunoreactive cells are observed in NP samples in comparison with patients with non-painful scoliosis [57]. It is worth noting that TNFR1 and TNFR2 along with TNF-α are comparably expressed in human NP tissues [56]. Furthermore, another study confirms the expression of both TNFR1 and TNFR2 in NP tissues obtained from patients with lumbar disc herniation, with levels of TNFR1 being positively correlated with severity of postoperative pain [58].…”

“…Moreover, the levels of TNF-α are significantly increased in degenerative IVD tissues when compared with non-degenerative samples, and TNF-α levels show a positive correlation with the degree of disc degeneration. A later study by Bachmeier et al [56] shows a higher expression of TNF-α in NP tissues compared with AF tissues, suggesting that the distribution of TNF-α within the discs is associated with tissue types. In patients with lumbar disc herniation, more TNF-α-immunoreactive cells are observed in NP samples in comparison with patients with non-painful scoliosis [57].…”

Molecular Mechanisms of Intervertebral Disc Degeneration

“…141 Symptomatic discs have been shown to have higher levels of pro-inflammatory cytokines, TNF-α, IL1β, IL-6, and IL-8, which are considered be associated with the NF-kB pathway. [127][128]156,[162][163] Mitogen-Activated Protein Kinases (MAPKs), a family of signal transduction pathways, allow cells to respond to extracellular inputs, including inflammatory cytokines and environmental stress. 164,165 Specifically, the expression of p38 MAPK, a subfamily of MAPK, has been described in senescent AF cells.…”