Intervertebral disc degeneration
Lumbar foraminal stenosis (LFS) is one of the most frequent forms of lumbar degenerative spondylosis (LDS), a late consequence of intervertebral disc degeneration (IVD) and considered a wear-and-tear phenomenon that is at least partially age-related. The narrowing of the intervertebral space leads to secondary hypertrophy of the intervertebral joints as a reaction to overload, ligamentous overgrowth, and a reduction in intervertebral foramen diameter. This chain reaction is the main reason for nerve root impingement and distorted neurodynamics that lead to mixed pain in advanced spondylosis (axial and radicular pain) 1).
Degeneration of one or more intervertebral disc(s), often called “degenerative disc disease” (DDD) or “degenerative disc disorder, is a disease of aging, and though for most people is not a problem, in certain individuals a degenerated disc can cause severe chronic pain if left untreated.
Its one of the most common causes of low back pain and neck pain, and a socioeconomic burden worldwide.
Degradation of the nucleus pulposus (NP) is an early hallmark of intervertebral disc degeneration.
Intervertebral disc degeneration is associated with disc herniation.
Occurring in 40% of individuals younger than 30 and more than 90% of those older than 50 years of age 2) , degenerative disc disease (DDD) is a prevalent clinical condition that can lead to nerve compression and chronic back pain.
Classification
Etiology
Pathogenesis
Cartilage endplate degeneration and calcification is an important contributor to the onset and pathogenesis of intervertebral disc degeneration (IDD). However, the underlying mechanisms of CEP degeneration remain elusive, let alone according treatment strategies to prevent CEP degeneration. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and recent studies indicated that PTEN is overexpressed in degenerated intervertebral disc. However, whether direct inhibition of PTEN attenuates CEP degeneration and IDD development remains largely unknown.
In vivo experiments demonstrated that VO-OHpic could attenuate IDD progression and CEP calcification. Cui et al. also found that VO-OHpic inhibited oxidative stress induced chondrocytes apoptosis and degeneration by activating Nrf-2/HO-1 pathway, thus promoted parkin mediated mitophagy process and inhibited chondrocytes ferroptosis, alleviated redox imbalance and eventually improved cell survival. Nrf-2 siRNA transfection significantly reversed the protective effect of VO-OHpic on endplate chondrocytes. In conclusion, the study demonstrated that inhibition of PTEN with VO-OHpic attenuates CEP calcification and IDD progression. Moreover, VO-OHpic protects endplate chondrocytes against apoptosis and degeneration via activating Nrf-2/HO-1 mediated mitophagy process and ferroptosis inhibition. The results suggest that VO-OHpic may be a potential effective medicine for IDD prevention and treatment 3).
Pathophysiology
Degeneration of intervertebral disc (IVD) tissue is characterized by several structural changes that result in variations in disc physiology and loss of biomechanical function. The complex process of degeneration exhibits highly intercorrelated biomechanical, biochemical, and cellular interactions. There is currently some understanding of the cellular changes in degenerated intervertebral disc tissue, but microstructural changes and deterioration of the tissue matrix have previously been rarely explored.
In a work, sequestered IVD tissue was successfully characterized using histology, light microscopy, and scanning electron microscopy (SEM) to quantitatively evaluate parameters of interest for intervertebral disc degeneration (IDD) such as delamination of the collagenous matrix, cell density, cell size, and extracellular matrix (ECM) thickness. Additional qualitative parameters investigated included matrix fibration and irregularity, neovascularization of the IVD, granular inclusions in the matrix, and cell cluster formation. The results of this study corroborated several previously published findings, including that positively correlating female gender and IVD cell density, age and cell size, and female gender and ECM thickness. Additionally, an array of quantitative and qualitative investigations of IVD degeneration could be successfully evaluated using the given methodology, resin-embedded SEM in particular. SEM is especially practical for studying micromorphological changes in tissue, as other microscopy methods can cause artificial tissue damage due to the preparation method. Investigation of the microstructural changes occurring in degenerated tissue provides a greater understanding of the complex process of disc degeneration as a whole. Developing a more complete picture of the degenerative changes taking place in the intervertebral disc is crucial for the advancement and application of regenerative therapies based on the pathology of intervertebral disc degeneration 4).
Bioinformatic analysis of the gene expression profiles
Herniation of nuclear or disc material along with inflammatory chemokines such as prostaglandin E2, interleukin-6, matrix metalloproteinase and nitric oxide has definite correlations, possibly they are over produced 5).
The gene expression profiles data were obtained using the same microarray platform for two groups of patients suffering from degenerative disc diseases: GSE41883 (Human annulus disc cells exposed to TNF-a; 4 samples) and GSE27494 (Human annulus disc cells exposed to IL-1β;; 4 samples). The genes that were differentially expressed in these two datasets compared to control disc cells (without cytokine exposure; 4 samples each) were identified using the R language, and were pooled using the Excel software program to select the common differentially expressed genes in the two datasets. The initial functional clustering, signaling pathways and protein-protein interaction relationship analyses were conducted using the DAVID and STRING software programs.
Of the 255 concomitantly and differentially expressed genes identified after respective treatment with TNF-α and IL-1β, 141 were up-regulated and 114 were down-regulated. The gene ontology annotation analysis showed that these differentially expressed genes were primarily associated with cytokine activity, growth factor activity, the inflammatory reaction and the response to injury. The signaling pathway analysis showed that these differentially expressed genes were mainly related to the interactions of cytokines, apoptosis and NOD-like receptor signaling pathways. The interaction network analysis indicated that PTGS2, ICAM1, NOV and other genes may play a role in disc degeneration.
ICAM1 and other genes may play a role in the development of disc degeneration induced by inflammatory reactions using a bioinformatics analysis of the gene expression profiles of degenerative intervertebral disc cells stimulated with inflammatory factors, suggesting that bioinformatics methods can be used to identify potential target for intervertebral disc degeneration 6).