Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration.
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, senescence-associated beta-galactosidase (SA-beta-gal), and replicative potential. Expression of P16INK4A (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 P16INK4A. Mean telomere length decreased with age in cells from non-degenerate tissue and also decreased with progressive stages of degeneration. In non-degenerate discs, there was an age-related increase in cellular expression of P16INK4A. Cells from degenerate discs (even from young patients) exhibited increased expression of P16INK4A, increased SA-beta-gal staining, and a decrease in replicative potential. Importantly, there was a positive correlation between P16INK4A 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.
Le Maitre
Christine Lyn
CL
Tissue Injury and Repair Group, School of Medicine, Stopford Building, The University of Manchester, Oxford Road, Manchester, UK, M13 9PT.
Freemont
Anthony John
AJ
Hoyland
Judith Alison
JA
D051722:ADAM Proteins / Q000096:biosynthesis; D000071116:ADAMTS5 Protein; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging; D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007403:Intervertebral Disc / Q000378:metabolism / Q000473:pathology*; D017116:Low Back Pain; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013122:Spinal Diseases / Q000378:metabolism / Q000473:pathology*; D016615:Telomere / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D001616:beta-Galactosidase; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D053509:Matrix Metalloproteinase 13