Wnt/β-catenin及NF-кB信号通路与椎间盘退变的研究进展_《中国修复重建外科杂志》

作者：

孔敬波 ^1,2 , 马信龙 ^1,2 , 王涛 ¹ , 马剑雄 ² , 田鹏 ¹ , 韩超 ¹ , 臧加成 ¹ , 李鹏飞 ² , 姜宏强 ²

1天津医院天津市中西医结合骨科研究所（天津，300211）;;
2天津医科大学总医院骨科骨科生物力学实验室;

关键词：

Wnt/β-catenin NF-κB 椎间盘退变信号通路

DOI：

10.7507/1002-1892.20130333

视频：

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摘要 全文 图表 视频 参考文献 施引文献 补充材料

目的综述Wnt/β-catenin及NF-кB信号通路在椎间盘退变过程中作用机制的研究进展。方法查阅Wnt/β-catenin及NF-кB信号通路在椎间盘退变过程中作用的相关文献，并进行分析总结。结果 Wnt/β-catenin及NF-кB信号通路在椎间盘退变过程中均被激活，且存在相互作用，但是它们在椎间盘退变过程中的具体作用机制以及相互作用的中间介质尚不清楚。结论 Wnt/β-catenin及NF-кB信号通路在椎间盘退变过程中的作用仍需深入研究。

引用本文： 孔敬波,马信龙,王涛,马剑雄,田鹏,韩超,臧加成,李鹏飞,姜宏强. Wnt/β-catenin及NF-кB信号通路与椎间盘退变的研究进展. 中国修复重建外科杂志, 2013, 27(12): 1523-1527. doi: 10.7507/1002-1892.20130333 复制

1.	Richardson SM, Doyle P, Minogue BM, et al. Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc. Arthritis Res Ther, 2009, 11(4): R126.
2.	Wu Q, Zhu M, Rosier RN, et al. Beta-catenin, cartilage, and osteoarthritis. Ann N Y Acad Sci, 2010, 1192: 344-350.
3.	Behari J. The Wnt/beta-catenin signaling pathway in liver biology and disease. Expert Rev Gastroenterol Hepatol, 2010, 4(6): 745-756.
4.	MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 2009, 17(1): 9-26.
5.	Ahn KS, Sethi G, Aggarwal BB. Nuclear factor-kappa B: from clone to clinic. Curr Mol Med, 2007, 7(7): 619-637.
6.	Kondo N, Yuasa T, Shimono K, et al. Intervertebral disc development is regulated by Wnt/β-catenin signaling. Spine (Phila Pa 1976), 2011, 36(8): E513-518.
7.	Nerlich AG, Bachmeier BE, Schleicher E, et al. Immunomorphological analysis of RAGE receptor expression and NF-kappa B activation in tissue samples from normal and degenerated intervertebral discs of various ages. Ann N Y Acad Sci, 2007, 1096: 239-248.
8.	Neumann J, Endermann T, Ehlers S, et al. Inverse relationship of TLR/NF-κB signalling and the Wnt/β-catenin pathway during inflammation: Deciphering the role of Frizzled1 in M.tuberculosis infection. Cell Communication and Signaling, 2009, 7(Suppl 1): A52.
9.	Du Q, Zhang X, Cardinal J, et al. Wnt/beta-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-kappaB activation in cancer cells. Cancer Res, 2009, 69(9): 3764-3771.
10.	Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976), 2006, 31(18): 2151-2161.
11.	Ahn SH, Cho YW, Ahn MW, et al. mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine (Phila Pa 1976), 2002, 27(9): 911-917.
12.	Le Maitre CL, Freemont AJ, Hoyland JA. The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther, 2005, 7(4): R732-745.
13.	Séguin CA, Pilliar RM, Roughley PJ, et al. Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine (Phila Pa1976), 2005, 30(17): 1940-1948.
14.	Nusse R, Varmre HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982, 31(1): 99-109.
15.	Sharma RP. Wingless a new mutant in Drosophila melanogaster. Drosophila Information Service, 1973, 50: 134.
16.	Seto ES, Bellen HJ. The ins and outs of wingless signaling. Trends Cell Biol, 2004, 14(1): 45-53.
17.	Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell, 1986, 46(5): 705-716.
18.	Mankan AK, Lawless MW, Gray SG, et al. NF-kappaB regulation: the nuclear response. J Cell Mol Med, 2009, 13(4): 631-643.
19.	王晶. 经典 Wnt/β-catenin 信号通路在椎间盘退变中的作用及机制研究. 武汉: 华中科技大学, 2009.
20.	Hiyama A, Sakai D, Risbud M, et al. Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling induced matrix metalloproteinase expression. Arthritis Rheum, 2010, 62(10): 3036-3047.
21.	Smolders LA, Meij BP, Onis D, et al. Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: implications for development of regenerative strategies. Arthritis Res Ther, 2013, 15 (1): R23.
22.	Mengshol JA, Vincenti MP, Coon CI, et al. Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor kappaB: differential regulation of collagenase 1 and collagenase 3. Arthritis Rheum, 2000, 43(19): 801-811.
23.	吴庆能, 雷刚刚, 钟青山, 等. 退变椎间盘中NF-κB、MMP-13的表达及意义. 实用临床医学, 2009, 10(2): 5-7.
24.	Yu ZG, Xu N, Wang WB, et al. Interleukin-1 inhibits Sox9 and collagen type II expression via nuclear factor-κB in the cultured human intervertebral disc cells. Chin Med J (Engl), 2009, 122(20): 2483-2488.
25.	原野, 赵静, 李永民. 核因子κB和肿瘤坏死因子仅在正常椎间盘及其退行性变组织中的表达. 中国临床康复, 2006, 10(28): 22, 25.
26.	Wang P, Qiu W, Dudgeon C, et al. PUMA is directly activated by NF-κB and contributes to TNF-alpha-induced apoptosis. Cell Death Differ, 2009, 16(9): 1192-1202.
27.	Wang J, Markova D, Anderson DG, et al. TNF-α and IL-1β promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. J Biol Chem, 2011, 286(46): 39738-39749.
28.	Nasto LA, Seo HY, Robinson AR, et al. Issls prize winner: Inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging. Spine (Phila Pa 1976), 2012, 37(21): 1819-1825.
29.	Fujita N, Markova D, Anderson DG, et al. Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: distinct roles of PHD2 and PHD3 proteins in controlling HIF-1α activity in hypoxia. Biol Chem, 2012, 287(20): 16975-16986.
30.	Fujita N, Chiba K, Shapiro IM, et al. HIF-1α and HIF-2α degradation is differentially regulated in nucleus pulposus cells of the intervertebral disc. J Bone Miner Res, 2012, 27(2): 401-412.
31.	Fujita N, Gogate SS, Chiba K, et al. Prolylhydroxylase-3 (PHD3) modulates catabolic effects of tumor necrosis factor-α (TNF-α) on cells of the nucleus pulposus through co-activation of nuclear factor κB (NF-κB)/p65 signaling. J Biol Chem, 2012, 287(47): 39942-39953.
32.	Moreau M, Mourah S, Dosquet C. β-Catenin and NF-κB cooperate to regulate the uPA/uPAR system in cancer cells. Int J Cancer, 2011, 128(6): 1280-1292.
33.	Carayol N, Wang CY. IKKalpha stabilizes cytosolic beta-catenin by inhibiting both canonical and non-canonical degradation pathways. Cell Signal, 2006, 18(11): 1941-1946.
34.	Lamberti C, Lin KM, Yamamoto Y, et al. Regulation of beta-catenin function by the IkappaB kinases. J Biol Cell, 2001, 276(45): 42276-42286.
35.	Albanese C, Wu K, D’Amico M, et al. IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf. Mol Biol Cell, 2003, 14(2): 585-599.
36.	Deng J, Miller SA, Wang HY, et al. beta-catenin interacts with and inhibits NF-kappa B in human colon and breast cancer. Cancer Cell, 2002, 2(4): 323-334.
37.	Deng J, Xia W, Miller SA, et al. Crossregulation of NF-κB by the APC/GSK-3beta/beta-catenin pathway. Mol Carcinog, 2004, 39(3): 139-146.
38.	Nejak-Bowen K, Kikuchi A, Monga SP. Beta-catenin-NF-κB interactions in murine hepatocytes: a complex to die for it . Hepatology, 2013, 57(2): 763-774.
39.	Deregowski V, Delhalle S, Benoit V, et al. Identification of cytokine-induced nuclear factor-kappaB target genes in ovarian and breast cancer cells. Biochem Pharmacol, 2002, 64(5-6): 873-881.
40.	Galbiati F, Volonate D, Brown AM, et al. Caveolin-1 expression inhibits Wnt/beta-catenin/Lef-1 signaling by recruiting beta-catenin to caveolae membrane domains. J Biol Chem, 2000, 275(30): 23368-23377.
41.	Wang CY, Mayo MW, Korneluk RG, et al. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science, 1998, 281(5383): 1680-1683.
42.	Greenspan EJ, Madigan JP, Boardman LA, et al. Ibuprofen inhibits activation of nuclear β-catenin in human colon adenomas and induces the phosphorylation of GSK-3β. Cancer Prev Res (Phila), 2011, 4(1): 161-171.
43.	Garrean S, Gao XP, Brovkovych V, et al. Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide. J Immunol, 2006, 177(7): 4853-4860.
44.	Ichimura A, Ruike Y, Terasawa K, et al. miRNAs and regulation of cell signaling. FEBS J, 2011, 278(10): 1610-1618.
45.	Wang HQ, Yu XD, Liu ZH, et al. Deregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3. J Pathol, 2011, 225(2): 232-242.
46.	Roccaro AM, Sacco A, Chen C, et al. microRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia. Blood, 2009, 113(18): 4391-4402.
47.	Zhang Y, Wei W, Cheng N, et al. Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology, 2012, 56(5): 1631-1640.
48.	Lu F, Weidmer A, Liu CG, et al. Epstein-Barr virus-induced miR-155 attenuates NF-κB signaling and stabilizes latent virus persistence. J Virol, 2008, 82(21): 10436-10443.
49.	Gortazar AR, Martin-Millan M, Bravo B, et al. Crosstalk between Caveolin-1/Extracellular Signal-regulated Kinase (ERK) and β-Catenin Survival Pathways in Osteocyte Mechanotransduction. J Biol Chem, 2013, 288(12): 8168-8175.

1. Richardson SM, Doyle P, Minogue BM, et al. Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc. Arthritis Res Ther, 2009, 11(4): R126.
2. Wu Q, Zhu M, Rosier RN, et al. Beta-catenin, cartilage, and osteoarthritis. Ann N Y Acad Sci, 2010, 1192: 344-350.
3. Behari J. The Wnt/beta-catenin signaling pathway in liver biology and disease. Expert Rev Gastroenterol Hepatol, 2010, 4(6): 745-756.
4. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 2009, 17(1): 9-26.
5. Ahn KS, Sethi G, Aggarwal BB. Nuclear factor-kappa B: from clone to clinic. Curr Mol Med, 2007, 7(7): 619-637.
6. Kondo N, Yuasa T, Shimono K, et al. Intervertebral disc development is regulated by Wnt/β-catenin signaling. Spine (Phila Pa 1976), 2011, 36(8): E513-518.
7. Nerlich AG, Bachmeier BE, Schleicher E, et al. Immunomorphological analysis of RAGE receptor expression and NF-kappa B activation in tissue samples from normal and degenerated intervertebral discs of various ages. Ann N Y Acad Sci, 2007, 1096: 239-248.
8. Neumann J, Endermann T, Ehlers S, et al. Inverse relationship of TLR/NF-κB signalling and the Wnt/β-catenin pathway during inflammation: Deciphering the role of Frizzled1 in M.tuberculosis infection. Cell Communication and Signaling, 2009, 7(Suppl 1): A52.
9. Du Q, Zhang X, Cardinal J, et al. Wnt/beta-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-kappaB activation in cancer cells. Cancer Res, 2009, 69(9): 3764-3771.
10. Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976), 2006, 31(18): 2151-2161.
11. Ahn SH, Cho YW, Ahn MW, et al. mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine (Phila Pa 1976), 2002, 27(9): 911-917.
12. Le Maitre CL, Freemont AJ, Hoyland JA. The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther, 2005, 7(4): R732-745.
13. Séguin CA, Pilliar RM, Roughley PJ, et al. Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine (Phila Pa1976), 2005, 30(17): 1940-1948.
14. Nusse R, Varmre HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982, 31(1): 99-109.
15. Sharma RP. Wingless a new mutant in Drosophila melanogaster. Drosophila Information Service, 1973, 50: 134.
16. Seto ES, Bellen HJ. The ins and outs of wingless signaling. Trends Cell Biol, 2004, 14(1): 45-53.
17. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell, 1986, 46(5): 705-716.
18. Mankan AK, Lawless MW, Gray SG, et al. NF-kappaB regulation: the nuclear response. J Cell Mol Med, 2009, 13(4): 631-643.
19. 王晶. 经典 Wnt/β-catenin 信号通路在椎间盘退变中的作用及机制研究. 武汉: 华中科技大学, 2009.
20. Hiyama A, Sakai D, Risbud M, et al. Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling induced matrix metalloproteinase expression. Arthritis Rheum, 2010, 62(10): 3036-3047.
21. Smolders LA, Meij BP, Onis D, et al. Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: implications for development of regenerative strategies. Arthritis Res Ther, 2013, 15 (1): R23.
22. Mengshol JA, Vincenti MP, Coon CI, et al. Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor kappaB: differential regulation of collagenase 1 and collagenase 3. Arthritis Rheum, 2000, 43(19): 801-811.
23. 吴庆能, 雷刚刚, 钟青山, 等. 退变椎间盘中NF-κB、MMP-13的表达及意义. 实用临床医学, 2009, 10(2): 5-7.
24. Yu ZG, Xu N, Wang WB, et al. Interleukin-1 inhibits Sox9 and collagen type II expression via nuclear factor-κB in the cultured human intervertebral disc cells. Chin Med J (Engl), 2009, 122(20): 2483-2488.
25. 原野, 赵静, 李永民. 核因子κB和肿瘤坏死因子仅在正常椎间盘及其退行性变组织中的表达. 中国临床康复, 2006, 10(28): 22, 25.
26. Wang P, Qiu W, Dudgeon C, et al. PUMA is directly activated by NF-κB and contributes to TNF-alpha-induced apoptosis. Cell Death Differ, 2009, 16(9): 1192-1202.
27. Wang J, Markova D, Anderson DG, et al. TNF-α and IL-1β promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. J Biol Chem, 2011, 286(46): 39738-39749.
28. Nasto LA, Seo HY, Robinson AR, et al. Issls prize winner: Inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging. Spine (Phila Pa 1976), 2012, 37(21): 1819-1825.
29. Fujita N, Markova D, Anderson DG, et al. Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: distinct roles of PHD2 and PHD3 proteins in controlling HIF-1α activity in hypoxia. Biol Chem, 2012, 287(20): 16975-16986.
30. Fujita N, Chiba K, Shapiro IM, et al. HIF-1α and HIF-2α degradation is differentially regulated in nucleus pulposus cells of the intervertebral disc. J Bone Miner Res, 2012, 27(2): 401-412.
31. Fujita N, Gogate SS, Chiba K, et al. Prolylhydroxylase-3 (PHD3) modulates catabolic effects of tumor necrosis factor-α (TNF-α) on cells of the nucleus pulposus through co-activation of nuclear factor κB (NF-κB)/p65 signaling. J Biol Chem, 2012, 287(47): 39942-39953.
32. Moreau M, Mourah S, Dosquet C. β-Catenin and NF-κB cooperate to regulate the uPA/uPAR system in cancer cells. Int J Cancer, 2011, 128(6): 1280-1292.
33. Carayol N, Wang CY. IKKalpha stabilizes cytosolic beta-catenin by inhibiting both canonical and non-canonical degradation pathways. Cell Signal, 2006, 18(11): 1941-1946.
34. Lamberti C, Lin KM, Yamamoto Y, et al. Regulation of beta-catenin function by the IkappaB kinases. J Biol Cell, 2001, 276(45): 42276-42286.
35. Albanese C, Wu K, D’Amico M, et al. IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf. Mol Biol Cell, 2003, 14(2): 585-599.
36. Deng J, Miller SA, Wang HY, et al. beta-catenin interacts with and inhibits NF-kappa B in human colon and breast cancer. Cancer Cell, 2002, 2(4): 323-334.
37. Deng J, Xia W, Miller SA, et al. Crossregulation of NF-κB by the APC/GSK-3beta/beta-catenin pathway. Mol Carcinog, 2004, 39(3): 139-146.
38. Nejak-Bowen K, Kikuchi A, Monga SP. Beta-catenin-NF-κB interactions in murine hepatocytes: a complex to die for it . Hepatology, 2013, 57(2): 763-774.
39. Deregowski V, Delhalle S, Benoit V, et al. Identification of cytokine-induced nuclear factor-kappaB target genes in ovarian and breast cancer cells. Biochem Pharmacol, 2002, 64(5-6): 873-881.
40. Galbiati F, Volonate D, Brown AM, et al. Caveolin-1 expression inhibits Wnt/beta-catenin/Lef-1 signaling by recruiting beta-catenin to caveolae membrane domains. J Biol Chem, 2000, 275(30): 23368-23377.
41. Wang CY, Mayo MW, Korneluk RG, et al. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science, 1998, 281(5383): 1680-1683.
42. Greenspan EJ, Madigan JP, Boardman LA, et al. Ibuprofen inhibits activation of nuclear β-catenin in human colon adenomas and induces the phosphorylation of GSK-3β. Cancer Prev Res (Phila), 2011, 4(1): 161-171.
43. Garrean S, Gao XP, Brovkovych V, et al. Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide. J Immunol, 2006, 177(7): 4853-4860.
44. Ichimura A, Ruike Y, Terasawa K, et al. miRNAs and regulation of cell signaling. FEBS J, 2011, 278(10): 1610-1618.
45. Wang HQ, Yu XD, Liu ZH, et al. Deregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3. J Pathol, 2011, 225(2): 232-242.
46. Roccaro AM, Sacco A, Chen C, et al. microRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia. Blood, 2009, 113(18): 4391-4402.
47. Zhang Y, Wei W, Cheng N, et al. Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology, 2012, 56(5): 1631-1640.
48. Lu F, Weidmer A, Liu CG, et al. Epstein-Barr virus-induced miR-155 attenuates NF-κB signaling and stabilizes latent virus persistence. J Virol, 2008, 82(21): 10436-10443.
49. Gortazar AR, Martin-Millan M, Bravo B, et al. Crosstalk between Caveolin-1/Extracellular Signal-regulated Kinase (ERK) and β-Catenin Survival Pathways in Osteocyte Mechanotransduction. J Biol Chem, 2013, 288(12): 8168-8175.

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Wnt/β-catenin及NF-кB信号通路与椎间盘退变的研究进展

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《中国修复重建外科杂志》

Wnt/β-catenin及NF-кB信号通路与椎间盘退变的研究进展

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