Our data show that fibrous nuclear transformation during aging/degeneration precedes cleft formation. The temporal sequence suggests a strong correlation of cleft and tears formation starting with clefts in the second decade. Our results support the hypothesis that disc degeneration starts in the nucleus. Extensive macroscopic alterations already apparent in the second life decade present a challenge to any tissue engineering and repair attempt.
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.
Recent advances in molecular biology, cell biology and material sciences have opened a new emerging field of techniques for the treatment of musculoskeletal disorders. These new treatment modalities aim for biological repair of the affected tissues by introducing cell-based tissue replacements, genetic modifications of resident cells or a combination thereof. So far, these techniques have been successfully applied to various tissues such as bone and cartilage. However, application of these treatment modalities to cure intervertebral disc degeneration is in its very early stages and mostly limited to experimental studies in vitro or in animal studies. We will discuss the potential and possible shortcomings of current approaches to biologically cure disc degeneration by gene therapy or tissue engineering. Despite the increasing number of studies examining the therapeutic potential of biological treatment strategies, a practicable solution to routinely cure disc degeneration might not be available in the near future. However, knowledge gained from these attempts might be applied in a foreseeable future to cure the low back pain that often accompanies disc degeneration and therefore be beneficial for the patient.
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.
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