Immunomorphological Analysis of RAGE Receptor Expression and NF‐κB Activation in Tissue Samples from Normal and Degenerated Intervertebral Discs of Various Ages

Abstract

We immunohistochemically investigated the pattern of RAGE expression and NFkappaB translocation into the nucleus in 43 complete cross-sections of human lumbar intervertebral discs (neonatal-85 years) and compared this with the carboxymethyl-lysine (CML) modification of proteins as a marker for oxidative stress. No significant expression of RAGE, no obvious activation of NF-kappaB, and no deposition of CML-modified proteins were seen in fetal, juvenile, and young adolescent discs (until age of 13 years). In adults, 25-50% of nucleus pulposus cells were labeled for RAGE and activated NF-kappaB, which correlated well with the occurrence and extent of CML staining in the pericellular matrix. In the annulus fibrosus significantly lower values were seen than in the nucleus pulposus. In consequence, we provide evidence for activation of the NF-kappaB system in intervertebral discs in vivo, which correlates with accumulated oxidative stress and increases in age and disc degeneration. Oxidative stress (as monitored by CML modifications) may lead to RAGE activation and NF-kappaB translocation.

Antioxidative nanofullerol prevents intervertebral disk degeneration

“…In recent years, numerous studies have demonstrated that oxidative stress plays an important role in the initiation and progression of disk degeneration. [16][17][18][19][20][21][22][23][24][25][26] These reports led us to seek an antioxidative therapy for alleviating oxidative stress on cells that may allow a slow but controlled regeneration of disk. The purpose of the present study was to investigate the potential therapeutic effects of an antioxidant compound on disk degeneration in vitro and in vivo.…”

“…14,15 In disk tissues, oxidative stress may initiate or participate in matrix destruction and cell apoptosis, which ultimately result in disk degeneration. 16 It has been shown that the increase of exogenous NO may promote cell apoptosis and suppress proteoglycan synthesis in cultured disk cells. NO has been demonstrated to participate in the disk degeneration induced by mechanical stress or interleukin (IL)-1.…”

“…The activation of RAGE-NFκB promoted the gene expression of nitric oxide synthase and MMPs. 16 It is not clear whether nanofullerol defends disk degeneration by modifying CML and its signaling pathway, and this is currently under investigation.…”

Molecular Basis of Intervertebral Disc Degeneration and Herniations: What Are the Important Translational Questions?

“…Oxidative stress is a known driver of cellular senescence and apoptosis. Higher levels of oxidized proteins and transcription factors activated by oxidative stresses have been found in older discs compared with young discs [64]. Other evidence of age-related oxidative damage in the disc is the presence of advanced glycalation endproducts, which are molecules produced by nonenzymatic glycosylation and oxidation of proteins and lipids [6,83].…”

Inflammatory and catabolic signalling in intervertebral discs: The roles of NF-B and MAP Kinases

“…Furthermore, more "modern" pharmaceuticals, such as the COX-2 inhibitor rofecoxib, can infl uence NF-B activity, e.g. in this case by inhibiting its DNA binding capacity (Niederberger et al, 2003). On the other hand, there are multiple "natural" candidates that seem to inhibit NF-κB in certain cell types, such as resveratrol (a polyphenol found in wine) (Holmes-McNary and Baldwin, 2000), curcumin (the main component of curcuma) (Jobin et al, 1999;Surh et al, 2000) or capsaicin (found in red pepper) (Surh et al, 2000).…”