RESEARCH PROGRESS OF CELLULAR SENESCENCE AND SENESCENT SECRETARY PHENOTYPE IN INTERVERTEBRAL DISC DEGENERATION_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WANG Feng ¹ , ZHENG Chenjingmei ² , WU Xiaotao ¹

1Department of Orthopaedics, Affiliated Zhongda Hospital of Southeast University, Nanjing Jiangsu, 210009, P.R.China;;
2Institute of Thoracic and Cardiovascular Surgery, Nanjing First Hospital Affiliated to Nanjing Medical University. Corresponding author: WU Xiaotao, E-mail: wuxiaotao@medmail.com.cn;

Corresponding author：

Keywords：

Intervertebral disc degeneration; Cellular senescence; Senescent secretary phenotype

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Objective To summarize the role of cellular senescence and senescent secretary phenotype in the intervertebral disc (IVD) degeneration. Methods Relevant articles that discussed the roles of cellular senescence in the IVD degeneration were extensively reviewed, and retrospective and comprehensive analysis was performed. The senescent phenomenon during IVD degeneration, senescent secretary phenotype of the disc cells, senescent pathways within the IVD microenvironment, as well as the anti-senescent approaches for IVD regeneration were systematically reviewed. Results During aging and degeneration, IVD cells gradually and/or prematurely undergo senescence by activating p53-p21-retinoblastoma (RB) or p16INK4A-RB senescent pathways. The accumulation of senescent cells not only decreases the self-renewal ability of IVD, but also deteriorates the disc microenvironment by producing more inflammatory cytokines and matrix degrading enzymes. More specific senescent biomarkers are required to fully understand the phenotype change of senescent disc cells during IVD degeneration. Molecular analysis of the senescent disc cells and their intracellular signaling pathways are needed to get a safer and more efficient anti-senescence strategy for IVD regeneration. Conclusion Cellular senescence is an important mechanism by which IVD cells decrease viability and degenerate biological behaviors, which provide a new thinking to understand the pathogenesis of IVD degeneration.

Citation： WANG Feng,ZHENG Chenjingmei,WU Xiaotao. RESEARCH PROGRESS OF CELLULAR SENESCENCE AND SENESCENT SECRETARY PHENOTYPE IN INTERVERTEBRAL DISC DEGENERATION. Chinese Journal of Reparative and Reconstructive Surgery, 2012, 26(12): 1448-1452. doi: Copy

1.	王锋, 王运涛, 吴小涛. 髓核细胞修复椎间盘退行性变的研究进展. 中国修复重建外科杂志, 2009, 23(7): 864-867.
2.	Wang F, Wu XT, Zhuang SY, et al. Ex vivo observation of human nucleus pulposus chondrocytes isolated from degenerated intervertebral discs. Asian Spine J, 2011, 5(2): 73-81.
3.	王锋, 吴小涛, 王运涛, 等. 非接触共培养条件下人BMSCs 对氧化应激环境中退变髓核细胞凋亡的保护研究. 中国修复重建外科杂志, 2010, 24(4): 391-398.
4.	Wang YT, Wu XT, Wang F. Regeneration potential and mechanism of bone marrow mesenchymal stem cell transplantation for treating intervertebral disc degeneration. J Orthop Sci, 2010, 15(6): 707-719.
5.	Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res, 1965, 37: 614-636.
6.	d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature, 2003, 426(6963): 194-198.
7.	Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol, 2005, 37(5): 961-976.
8.	Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell, 2005, 120(4): 513-522.
9.	Loeser RF. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage, 2009, 17(8): 971-979.
10.	Davalos AR, Coppe JP, Campisi J, et al. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev, 2010, 29(2): 273-283.
11.	Roberts S, Evans EH, Kletsas D, et al. Senescence in human intervertebral discs. Eur Spine J, 2006, 15 Suppl 3: S312-316.
12.	Qian Y, Chen X. Tumor suppression by p53: making cells senescent. Histol Histopathol, 2010, 25(4): 515-526.
13.	Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci, 1995, 92(20): 9363-9367.
14.	Itahana K, Campisi J, Dimri GP. Methods to detect biomarkers of cellular senescence: the senescence-associated beta-galactosidase assay. Methods Mol Biol, 2007, 371: 21-31.
15.	Gruber HE, Ingram JA, Norton HJ, et al. Senescence in cells of the aging and degenerating intervertebral disc: immunolocalization of senescence associated beta-galactosidase in human and sand rat discs. Spine (Phila Pa 1976), 2007, 32(3): 321-327.
16.	Gruber HE, Ingram JA, Davis DE, et al. Increased cell senescence is associated with decreased cell proliferation in vivo in the degenerating human annulus. Spine J, 2009, 9(3): 210-215.
17.	Gruber HE, Hoelscher GL, Ingram JA, et al. IGF-1 rescues human intervertebral annulus cells from in vitro stress-induced premature senescence. Growth Factors, 2008, 26(4): 220-225.
18.	Mavrogonatou E, Kletsas D. High osmolality activates the G1 and G2 cell cycle checkpoints and affects the DNA integrity of nucleus pulposus intervertebral disc cells triggering an enhanced DNA repair response. DNA Repair (Amst), 2009, 8(8): 930-943.
19.	Nakai T, Mochida J, Sakai D. Synergistic role of c-Myc and ERK1/2 in the mitogenic response to TGF beta-1 in cultured rat nucleus pulposus cells. Arthritis Res Ther, 2008, 10(6): R140.
20.	Le Maitre CL, Freemont AJ, Hoyland JA. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther, 2007, 9(3): R45.
21.	Kim KW, Chung HN, Ha KY, et al. Senescence mechanisms of nucleus pulposus chondrocytes in human intervertebral discs. Spine J, 2009, 9(8): 658-666.
22.	Heathfield SK, Le Maitre CL, Hoyland JA. Caveolin-1 expression and stress-induced premature senescence in human intervertebral disc degeneration. Arthritis Res Ther, 2008, 10(4): R87.
23.	周昊嵬, 侯树勋, 商卫林, 等. P16INK4A和Fas对椎间盘细胞功能影响的比较. 中华实验外科杂志, 2006, 23(12): 1505-1507.
24.	Evans EH, Kletsas D, Urban J, et al. The use of SA-β-Gal to assess cell senescence in intervertebral disc cells. Int J Exp Pathol, 2004, 85(4): A61-62.
25.	Johnson WE, Eisenstein SM, Roberts S. Cell cluster formation in degenerate lumbar intervertebral discs is associated with increased disc cell proliferation. Connect Tissue Res, 2001, 42(3): 197-207.
26.	Sharp CA, Roberts S, Evans H, et al. Disc cell clusters in pathological human intervertebral discs are associated with increased stress protein immunostaining. Eur Spine J, 2009, 18(11): 1587-1594.
27.	Nerlich AG, Bachmeier BE, Schleicher E, et al. Immunomorphological analysis of RAGE receptor expression and NF-kappaB activation in tissue samples from normal and degenerated intervertebral discs of various ages. Ann N Y Acad Sci, 2007, 1096: 239-248.
28.	Knudsen ES, Knudsen KE. Tailoring to RB: tumour suppressor status and therapeutic response. Nat Rev Cancer, 2008, 8(9): 714-724.
29.	Hiyama A, Sakai D, Risbud MV, et al. Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum, 2010, 62(10): 3036-3047.
30.	Gruber HE, Mougeot JL, Hoelscher G, et al. Microarray analysis of laser capture microdissected-anulus cells from the human intervertebral disc. Spine (Phila Pa 1976), 2007, 32(11): 1181-1187.
31.	Gruber HE, Hoelscher GL, Ingram JA, et al. Senescent vs. non-senescent cells in the human annulus in vivo: cell harvest with laser capture microdissection and gene expression studies with microarray analysis. BMC Biotechnol, 2010, 10: 5.
32.	Dang L, Liu Z. A review of current treatment for lumbar disc herniation in children and adolescents. Eur Spine J, 2010, 19(2): 205-214.
33.	Johnson WE, Stephan S, Roberts S. The influence of serum, glucose and oxygen on intervertebral disc cell growth in vitro: implications for degenerative disc disease. Arthritis Res Ther, 2008, 10(2): R46.
34.	Xing QJ, Liang QQ, Bian Q, et al. Leg amputation accelerates senescence of rat lumbar intervertebral discs. Spine (Phila Pa 1976), 2010, 35(23): E1253-1261.
35.	Chung SA, Wei AQ, Connor DE, et al. Nucleus pulposus cellular longevity by telomerase gene therapy. Spine (Phila Pa 1976), 2007, 32(11): 1188-1196.
36.	Sakai D, Mochida J, Yamamoto Y, et al. Immortalization of human nucleus pulposus cells by a recombinant SV40 adenovirus vector: establishment of a novel cell line for the study of human nucleus pulposus cells. Spine (Phila Pa 1976), 2004, 29(14): 1515-1523.
37.	Niu CC, Yuan LJ, Lin SS, et al. Mesenchymal stem cell and nucleus pulposus cell coculture modulates cell profile. Clin Orthop Relat Res, 2009, 467(12): 3263-3272.
38.	Hiyama A, Sakai D, Tanaka M, et al. The relationship between the Wnt/β-catenin and TGF-β/BMP signals in the intervertebral disc cell. J Cell Physiol, 2011, 226(5): 1139-1148.
39.	Katakura Y, Nakata E, Tabira Y, et al. Decreased tumorigenicity in vivo when transforming growth factor beta treatment causes cancer cell senescence. Biosci Biotechnol Biochem, 2003, 67(4): 815-821.
40.	Minagawa S, Araya J, Numata T, et al. Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2011, 300(3): L391-401.

1. 王锋, 王运涛, 吴小涛. 髓核细胞修复椎间盘退行性变的研究进展. 中国修复重建外科杂志, 2009, 23(7): 864-867.
2. Wang F, Wu XT, Zhuang SY, et al. Ex vivo observation of human nucleus pulposus chondrocytes isolated from degenerated intervertebral discs. Asian Spine J, 2011, 5(2): 73-81.
3. 王锋, 吴小涛, 王运涛, 等. 非接触共培养条件下人BMSCs 对氧化应激环境中退变髓核细胞凋亡的保护研究. 中国修复重建外科杂志, 2010, 24(4): 391-398.
4. Wang YT, Wu XT, Wang F. Regeneration potential and mechanism of bone marrow mesenchymal stem cell transplantation for treating intervertebral disc degeneration. J Orthop Sci, 2010, 15(6): 707-719.
5. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res, 1965, 37: 614-636.
6. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature, 2003, 426(6963): 194-198.
7. Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol, 2005, 37(5): 961-976.
8. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell, 2005, 120(4): 513-522.
9. Loeser RF. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage, 2009, 17(8): 971-979.
10. Davalos AR, Coppe JP, Campisi J, et al. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev, 2010, 29(2): 273-283.
11. Roberts S, Evans EH, Kletsas D, et al. Senescence in human intervertebral discs. Eur Spine J, 2006, 15 Suppl 3: S312-316.
12. Qian Y, Chen X. Tumor suppression by p53: making cells senescent. Histol Histopathol, 2010, 25(4): 515-526.
13. Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci, 1995, 92(20): 9363-9367.
14. Itahana K, Campisi J, Dimri GP. Methods to detect biomarkers of cellular senescence: the senescence-associated beta-galactosidase assay. Methods Mol Biol, 2007, 371: 21-31.
15. Gruber HE, Ingram JA, Norton HJ, et al. Senescence in cells of the aging and degenerating intervertebral disc: immunolocalization of senescence associated beta-galactosidase in human and sand rat discs. Spine (Phila Pa 1976), 2007, 32(3): 321-327.
16. Gruber HE, Ingram JA, Davis DE, et al. Increased cell senescence is associated with decreased cell proliferation in vivo in the degenerating human annulus. Spine J, 2009, 9(3): 210-215.
17. Gruber HE, Hoelscher GL, Ingram JA, et al. IGF-1 rescues human intervertebral annulus cells from in vitro stress-induced premature senescence. Growth Factors, 2008, 26(4): 220-225.
18. Mavrogonatou E, Kletsas D. High osmolality activates the G1 and G2 cell cycle checkpoints and affects the DNA integrity of nucleus pulposus intervertebral disc cells triggering an enhanced DNA repair response. DNA Repair (Amst), 2009, 8(8): 930-943.
19. Nakai T, Mochida J, Sakai D. Synergistic role of c-Myc and ERK1/2 in the mitogenic response to TGF beta-1 in cultured rat nucleus pulposus cells. Arthritis Res Ther, 2008, 10(6): R140.
20. Le Maitre CL, Freemont AJ, Hoyland JA. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther, 2007, 9(3): R45.
21. Kim KW, Chung HN, Ha KY, et al. Senescence mechanisms of nucleus pulposus chondrocytes in human intervertebral discs. Spine J, 2009, 9(8): 658-666.
22. Heathfield SK, Le Maitre CL, Hoyland JA. Caveolin-1 expression and stress-induced premature senescence in human intervertebral disc degeneration. Arthritis Res Ther, 2008, 10(4): R87.
23. 周昊嵬, 侯树勋, 商卫林, 等. P16INK4A和Fas对椎间盘细胞功能影响的比较. 中华实验外科杂志, 2006, 23(12): 1505-1507.
24. Evans EH, Kletsas D, Urban J, et al. The use of SA-β-Gal to assess cell senescence in intervertebral disc cells. Int J Exp Pathol, 2004, 85(4): A61-62.
25. Johnson WE, Eisenstein SM, Roberts S. Cell cluster formation in degenerate lumbar intervertebral discs is associated with increased disc cell proliferation. Connect Tissue Res, 2001, 42(3): 197-207.
26. Sharp CA, Roberts S, Evans H, et al. Disc cell clusters in pathological human intervertebral discs are associated with increased stress protein immunostaining. Eur Spine J, 2009, 18(11): 1587-1594.
27. Nerlich AG, Bachmeier BE, Schleicher E, et al. Immunomorphological analysis of RAGE receptor expression and NF-kappaB activation in tissue samples from normal and degenerated intervertebral discs of various ages. Ann N Y Acad Sci, 2007, 1096: 239-248.
28. Knudsen ES, Knudsen KE. Tailoring to RB: tumour suppressor status and therapeutic response. Nat Rev Cancer, 2008, 8(9): 714-724.
29. Hiyama A, Sakai D, Risbud MV, et al. Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum, 2010, 62(10): 3036-3047.
30. Gruber HE, Mougeot JL, Hoelscher G, et al. Microarray analysis of laser capture microdissected-anulus cells from the human intervertebral disc. Spine (Phila Pa 1976), 2007, 32(11): 1181-1187.
31. Gruber HE, Hoelscher GL, Ingram JA, et al. Senescent vs. non-senescent cells in the human annulus in vivo: cell harvest with laser capture microdissection and gene expression studies with microarray analysis. BMC Biotechnol, 2010, 10: 5.
32. Dang L, Liu Z. A review of current treatment for lumbar disc herniation in children and adolescents. Eur Spine J, 2010, 19(2): 205-214.
33. Johnson WE, Stephan S, Roberts S. The influence of serum, glucose and oxygen on intervertebral disc cell growth in vitro: implications for degenerative disc disease. Arthritis Res Ther, 2008, 10(2): R46.
34. Xing QJ, Liang QQ, Bian Q, et al. Leg amputation accelerates senescence of rat lumbar intervertebral discs. Spine (Phila Pa 1976), 2010, 35(23): E1253-1261.
35. Chung SA, Wei AQ, Connor DE, et al. Nucleus pulposus cellular longevity by telomerase gene therapy. Spine (Phila Pa 1976), 2007, 32(11): 1188-1196.
36. Sakai D, Mochida J, Yamamoto Y, et al. Immortalization of human nucleus pulposus cells by a recombinant SV40 adenovirus vector: establishment of a novel cell line for the study of human nucleus pulposus cells. Spine (Phila Pa 1976), 2004, 29(14): 1515-1523.
37. Niu CC, Yuan LJ, Lin SS, et al. Mesenchymal stem cell and nucleus pulposus cell coculture modulates cell profile. Clin Orthop Relat Res, 2009, 467(12): 3263-3272.
38. Hiyama A, Sakai D, Tanaka M, et al. The relationship between the Wnt/β-catenin and TGF-β/BMP signals in the intervertebral disc cell. J Cell Physiol, 2011, 226(5): 1139-1148.
39. Katakura Y, Nakata E, Tabira Y, et al. Decreased tumorigenicity in vivo when transforming growth factor beta treatment causes cancer cell senescence. Biosci Biotechnol Biochem, 2003, 67(4): 815-821.
40. Minagawa S, Araya J, Numata T, et al. Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2011, 300(3): L391-401.

Chinese Journal of Reparative and Reconstructive Surgery

RESEARCH PROGRESS OF CELLULAR SENESCENCE AND SENESCENT SECRETARY PHENOTYPE IN INTERVERTEBRAL DISC DEGENERATION

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