Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration

Abstract

Current evidence implicates intervertebral disc degeneration as a major cause of low back pain, although its pathogenesis is poorly understood. Numerous characteristic features of disc degeneration mimic those seen during ageing but appear to occur at an accelerated rate. We hypothesised that this is due to accelerated cellular senescence, which causes fundamental changes in the ability of disc cells to maintain the intervertebral disc (IVD) matrix, thus leading to IVD degeneration. Cells isolated from non-degenerate and degenerate human tissue were assessed for mean telomere length, senescenceassociated β-galactosidase (SA-β-gal), and replicative potential. Expression of P16 INK4A (increased in cellular senescence) was also investigated in IVD tissue by means of immunohistochemistry. RNA from tissue and cultured cells was used for real-time polymerase chain reaction analysis for matrix metalloproteinase-13, ADAMTS 5 (a disintegrin and metalloprotease with thrombospondin motifs 5), and P16 INK4A . Mean telomere length decreased with age in cells from nondegenerate tissue and also decreased with progressive stages of degeneration. In non-degenerate discs, there was an agerelated increase in cellular expression of P16 INK4A . Cells from degenerate discs (even from young patients) exhibited increased expression of P16 INK4A , increased SA-β-gal staining, and a decrease in replicative potential. Importantly, there was a positive correlation between P16 INK4A and matrix-degrading enzyme gene expression. Our findings indicate that disc cell senescence occurs in vivo and is accelerated in IVD degeneration. Furthermore, the senescent phenotype is associated with increased catabolism, implicating cellular senescence in the pathogenesis of IVD degeneration.

Disc cell clusters in pathological human intervertebral discs are associated with increased stress protein immunostaining

“…However, after proliferation disc cells may become senescent [6,12,18], a common finding in herniated discs [31]. Both Hsp27 and Hsp72 have been implicated in the regulation of cell proliferation, apoptosis and senescence [for reviews see 16 and 33].…”

The Role of Cell Clusters in Intervertebral Disc Degeneration and its Relevance behind Repair

“…Degenerative changes triggered by such intrinsic or extrinsic factors creates a stressful microenvironment for the disc cells and possibly reprograms it to increase synthesis of inflammatory cytokines [6,55] and may even allow it to enter into stages such as senescence [56,57]. The presence of senescence in the human disc cells has been shown by culturing them with B-galactosidase, and a recent study has shown that mean telomere length of the disc cells decreases as cellular expression of P16INK4A increases [58]. These studies show that cell senescence plays a direct role in disc aging and degeneration.…”

Spermidine promotes nucleus pulposus autophagy as a protective mechanism against apoptosis and ameliorates disc degeneration

“…These proteins aid in disc homoeostasis by blocking nerve ingrowth5 and disc calcification 6. Aberrant apoptosis within the nucleus pulposus is a key factor in the development of IDD and has been considered as a target for the treatment of disc degeneration 7, 8, 9…”