• 1東南大學附屬中大醫(yī)院骨科（南京，210009）;;
  • 2南京醫(yī)科大學附屬南京第一醫(yī)院心臟研究所;

目的綜述細胞老化及老化表型改變在椎間盤退行性變中的研究進展。 方法查閱椎間盤退行性變領(lǐng)域細胞老化相關(guān)的國內(nèi)外文獻并回顧分析，綜述椎間盤細胞的老化現(xiàn)象、老化表型改變、老化信號激活與椎間盤退行性變的相互關(guān)系，評價抗老化治療對椎間盤退行性變的修復作用。 結(jié)果隨著機體衰老與椎間盤退行性變，椎間盤細胞通過選擇性地激活p53-p21-視網(wǎng)膜母細胞瘤（retinoblastoma，RB）或p16INK4A-RB信號通路而老化。老化細胞的聚集不僅弱化了椎間盤的自我修復能力，同時上調(diào)表達炎性因子、基質(zhì)降解酶等老化分泌表型，從而進一步惡化鄰近細胞賴以生存的微環(huán)境。尋找老化細胞特異性的生化標記物是進一步探明椎間盤細胞老化分泌表型的關(guān)鍵，安全且高效的抗老化治療依賴于對椎間盤細胞老化機制的深入認識。 結(jié)論從細胞老化及老化表型改變角度認識椎間盤細胞活性丟失與功能改變的病理機制，為理解椎間盤退變性變的細胞學病因提供了新思路。

引用本文： 王鋒,鄭陳靜美,吳小濤. 細胞老化及老化表型改變在椎間盤退行性變中的研究進展. 中國修復重建外科雜志, 2012, 26(12): 1448-1452. doi: 復制

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1. 王鋒, 王運濤, 吳小濤. 髓核細胞修復椎間盤退行性變的研究進展. 中國修復重建外科雜志, 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. 王鋒, 吳小濤, 王運濤, 等. 非接觸共培養(yǎng)條件下人BMSCs 對氧化應激環(huán)境中退變髓核細胞凋亡的保護研究. 中國修復重建外科雜志, 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, 侯樹勛, 商衛(wèi)林, 等. P16INK4A和Fas對椎間盤細胞功能影響的比較. 中華實驗外科雜志, 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. 1. 王鋒, 王運濤, 吳小濤. 髓核細胞修復椎間盤退行性變的研究進展. 中國修復重建外科雜志, 2009, 23(7): 864-867.
  2. 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. 3. 王鋒, 吳小濤, 王運濤, 等. 非接觸共培養(yǎng)條件下人BMSCs 對氧化應激環(huán)境中退變髓核細胞凋亡的保護研究. 中國修復重建外科雜志, 2010, 24(4): 391-398.
  4. 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. 5. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res, 1965, 37: 614-636.
  6. 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. 7. Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol, 2005, 37(5): 961-976.
  8. 8. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell, 2005, 120(4): 513-522.
  9. 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. 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. 11. Roberts S, Evans EH, Kletsas D, et al. Senescence in human intervertebral discs. Eur Spine J, 2006, 15 Suppl 3: S312-316.
  12. 12. Qian Y, Chen X. Tumor suppression by p53: making cells senescent. Histol Histopathol, 2010, 25(4): 515-526.
  13. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 23. 周昊嵬, 侯樹勛, 商衛(wèi)林, 等. P16INK4A和Fas對椎間盤細胞功能影響的比較. 中華實驗外科雜志, 2006, 23(12): 1505-1507.
  24. 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. 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. 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. 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. 28. Knudsen ES, Knudsen KE. Tailoring to RB: tumour suppressor status and therapeutic response. Nat Rev Cancer, 2008, 8(9): 714-724.
  29. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.