Abstract
Low back pain is a major cause of disability especially for people between 20 and 50 years of age. As a costly healthcare problem, it imposes a serious socio-economic burden. Current surgical therapies fail to replace the normal disc in facilitating spinal movements and absorbing load. The focus of regenerative medicine is on identifying biomarkers and signalling pathways to improve our understanding about cascades of disc degeneration and allow for the design of specific therapies. We hypothesized that comparing microarray profiles from degenerative and non-degenerative discs will lead to the identification of dysregulated signalling and pathophysiological targets. Microarray data sets were generated from human annulus fibrosus cells and analysed using IPA ingenuity pathway analysis. Gene expression values were validated by qRT-PCR, and respective proteins were identified by immunohistochemistry. Microarray analysis revealed 238 differentially expressed genes in the degenerative annulus fibrosus. Seventeen of the dysregulated molecular markers showed log2-fold changes greater than ±1.5. Various dysregulated cellular functions, including cell proliferation and inflammatory response, were identified. The most significant canonical pathway induced in degenerative annulus fibrosus was found to be the interferon pathway. This study indicates interferon-alpha signalling pathway activation with IFIT3 and IGFBP3 up-regulation, which may affect cellular function in human degenerative disc.
Highlights
Current surgical therapy options include the removal of the degenerated or herniated tissue or even the partial or complete replacement of the disc with an artificial substitute[8]
Analysis of the data obtained from the microarray profiling of 16 degenerative and 8 non-degenerative samples led to the identification of 238 significantly differentially expressed genes in the degenerative human annulus fibrosus (Supplementary Table 1)
Disc degeneration is a chronic disease that involves different factors leading to the decrease in the number of disc cells and eventually to ECM degradation, neural invasion and low back pain[15,30]
Summary
Current surgical therapy options include the removal of the degenerated or herniated tissue or even the partial or complete replacement of the disc with an artificial substitute[8]. The abnormal cell-mediated response, the changes that occur in the extracellular matrix composition[11] and the diminished biomechanical characteristics[12], which can be induced by non-physiological mechanical loading[13], genetic predisposition and decreased cell activity[14], lead to gradual structural failure of the IVD This condition defines the degenerative disc disease (DDD) that goes along with nerve in-growth and low back pain[15]. Following on from the single gene alterations, we focussed on perturbations in molecular and cellular functions and signalling pathways in the degenerative AF As such the objectives of this study were (1) to highlight the most dysregulated molecular markers and cellular functions in the human degenerative annulus fibrosus and (2) to identify the activated catabolic pathway(s) through the involved dysregulated molecular markers. This pathway may be targeted with a well-designed therapeutic agent at early stages of degeneration
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