RESEARCH PROGRESS OF REGULATION EFFECT OF HYPOXIA INDUCIBLE FACTOR ON INTERVERTEBRAL DISC_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

CHENQi ^1,2 , MALongbing ^1,3 , YANGXi ¹ , LIULimin ¹ ,  SONGYueming ¹

1. Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P. R. China;
2. Department of Orthopedics, Zhejiang Provincial People's Hospital;
3. Department of Minimally Invasive Urology, Shandong Provincial Hospital;

Corresponding author：

SONGYueming, Email: hx_sym@163.com

Keywords：

Hypoxia inducible factor; Intervertebral disc; Nucleus pulposu; Regulation effect

DOI：

10.7507/1002-1892.20160263

Video：

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Objective To summarize the research progress of the regulation effect of hypoxia inducible factor (HIF) on intervertebral disc. Methods The domestic and foreign related literature about the regulation effect of HIF on intervertebral disc was reviewed, summarized, and analyzed. Results HIF is a key transcription factor that is in response to hypoxia by cells, which is widely distributed in tissues and organs, including intervertebral disc. Hypoxia inducible factor is expressed highest in the nucleus pulposus which has the lowest oxygen concentration in the intervertebral disc. The effects of HIF include the regulation of nucleus pulposus differentiation and development, maintenance of the survival, energy metabolism, and anabolism of nucleus pulposus cells, and maintenance of the stability of extracellular matrix. Conclusion HIF plays a vital role in the development and differentiation of intervertebral disc and maintenance of physiological function, which may become a target for the research of the mechanism and the treatment of intervertebral disc degeneration.

Citation： CHEN Qi, MA Longbing, YANG Xi, LIU Limin, SONG Yueming. RESEARCH PROGRESS OF REGULATION EFFECT OF HYPOXIA INDUCIBLE FACTOR ON INTERVERTEBRAL DISC. Chinese Journal of Reparative and Reconstructive Surgery, 2016, 30(10): 1295-1300. doi: 10.7507/1002-1892.20160263 Copy

1.	Kadow T, Sowa G, Vo N, et al. Molecular basis of intervertebral disc degeneration and herniations:what are the important translational questions? Clin Orthop Relat Res, 2014, 473(6):1903-1912.
2.	Phillips FM, An H, Kang JD, et al. Biologic treatment for intervertebral disc degeneration:summary statement. Spine (Phila Pa 1976), 2003, 28(15 Suppl):S99.
3.	Maniadakis N, Gray A. The economic burden of back pain in the UK. Pain, 2000, 84(1):95-103.
4.	Loenarz C, Coleman ML, Boleininger A, et al. The hypoxia-inducible transcription factor pathway regulates oxygen sensing in the simplest animal, Trichoplax adhaerens. EMBO Rep, 2011, 12(1):63-70.
5.	Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol, 1992, 12(12):5447-5454.
6.	Zhao J, Zhang P, Qin L, et al. Hypoxia is essential for bone-tendon junction healing:the molecular biological evidence. Int Orthop, 2011, 35(6):925-928.
7.	Fraisl P, Aragonés J, Carmeliet P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov, 2009, 8(2):139-152.
8.	Lin WP, Wang XJ, Wang CR, et al. Polymorphism in the hypoxia-inducible factor 1alpha gene may confer susceptibility to LDD in Chinese cohort. PLoS One, 2013, 8(8):e73158.
9.	Jiang BH, Semenza GL, Bauer C, et al. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol, 1996, 271(4 Pt 1):C1172-1180.
10.	Huang LE, Gu J, Schau M, et al. Regulation of hypoxia-inducible factor 1alpha is mediated by an O₂-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A, 1998, 95(14):7987-7992.
11.	Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 2001, 107(1):43-54.
12.	Kallio PJ, Wilson WJ, O'Brien S, et al. Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem, 1999, 274(10):6519-6525.
13.	Masson N, Ratcliffe PJ. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels. J Cell Sci, 2003, 116(Pt 15):3041-3049.
14.	Berra E, Benizri E, Ginouvès A, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J, 2003, 22(16):4082-4090.
15.	Lando D, Peet DJ, Whelan DA, et al. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science, 2002, 295(5556):858-861.
16.	Dunwoodie SL. The role of hypoxia in development of the Mammalian embryo. Dev Cell, 2009, 17(6):755-773.
17.	Iyer NV, Kotch LE, Agani F, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev, 1998, 12(2):149-162.
18.	Yoon D, Ponka P, Prchal JT. Hypoxia.5.Hypoxia and hematopoiesis. Am J Physiol Cell Physiol, 2011, 300(6):C1215-1222.
19.	Schipani E, Ryan HE, Didrickson S, et al. Hypoxia in cartilage:HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev, 2001, 15(21):2865-2876.
20.	Yun Z, Maecker HL, Johnson RS, et al. Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13:a mechanism for regulation of adipogenesis by hypoxia. Dev Cell, 2002, 2(3):331-341.
21.	Kojima H, Gu H, Nomura S, et al. Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha-deficient chimeric mice. Proc Natl Acad Sci U S A, 2002, 99(4):2170-2174.
22.	Dang EV, Barbi J, Yang HY, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell, 2011, 146(5):772-784.
23.	Wang Y, Wan C, Deng L, et al. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest, 2007, 117(6):1616-1626.
24.	Takubo K, Goda N, Yamada W, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell, 2010, 7(3):391-402.
25.	Zinkernagel AS, Johnson RS, Nizet V. Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med (Berl), 2007, 85(12):1339-1346.
26.	Gustafsson MV, Zheng X, Pereira T, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell, 2005, 9(5):617-628.
27.	Shimoda LA, Manalo DJ, Sham JS, et al. Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. Am J Physiol Lung Cell Mol Physiol, 2001, 281(1):L202-208.
28.	Yu AY, Shimoda LA, Iyer NV, et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J Clin Invest, 1999, 103(5):691-696.
29.	Kline DD, Peng YJ, Manalo DJ, et al. Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. Proc Natl Acad Sci U S A, 2002, 99(2):821-826.
30.	Genbacev O, Zhou Y, Ludlow JW, et al. Regulation of human placental development by oxygen tension. Science, 1997, 277(5332):1669-1672.
31.	Scheid A, Wenger RH, Schäffer L, et al. Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3. FASEB J, 2002, 16(3):411-413.
32.	Katz MM, Hargens AR, Garfin SR. Intervertebral disc nutrition. Diffusion versus convection. Clin Orthop Relat Res, 1986, (210):243-245.
33.	Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 2001, 294(5545):1337-1340.
34.	Loinard C, Ginouves A, Vilar J, et al. Inhibition of prolyl hydroxylase domain proteins promotes therapeutic revascularization. Circulation, 2009, 120(1):50-59.
35.	Hlatky MA, Quertermous T, Boothroyd DB, et al. Polymorphisms in hypoxia inducible factor 1 and the initial clinical presentation of coronary disease. Am Heart J, 2007, 154(6):1035-1042.
36.	Resar JR, Roguin A, Voner J, et al. Hypoxia-inducible factor 1alpha polymorphism and coronary collaterals in patients with ischemic heart disease. Chest, 2005, 128(2):787-791.
37.	Bosch-Marce M, Okuyama H, Wesley JB, et al. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res, 2007, 101(12):1310-1318.
38.	Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell, 2012, 148(3):399-408.
39.	Merceron C, Mangiavini L, Robling A, et al. Loss of HIF-1α in the notochord results in cell death and complete disappearance of the nucleus pulposus. PLoS One, 2014, 9(10):e110768.
40.	Agrawal A, Guttapalli A, Narayan S, et al. Normoxic stabilization of HIF-1alpha drives glycolytic metabolism and regulates aggrecan gene expression in nucleus pulposus cells of the rat intervertebral disk. Am J Physiol Cell Physiol, 2007, 293(2):C621-631.
41.	Ha KY, Koh IJ, Kirpalani PA, et al. The expression of hypoxia inducible factor-1alpha and apoptosis in herniated discs. Spine (Phila Pa 1976), 2006, 31(12):1309-1313.
42.	Agrawal A, Gajghate S, Smith H, et al. Cited2 modulates hypoxia-inducible factor-dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc. Arthritis Rheum, 2008, 58(12):3798-3808.
43.	Rajpurohit R, Risbud MV, Ducheyne P, et al. Phenotypic characteristics of the nucleus pulposus:expression of hypoxia inducing factor-1, glucose transporter-1 and MMP-2. Cell Tissue Res, 2002, 308(3):401-407.
44.	Risbud MV, Guttapalli A, Stokes DG, et al. Nucleus pulposus cells express HIF-1 alpha under normoxic culture conditions:a metabolic adaptation to the intervertebral disc microenvironment. J Cell Biochem, 2006, 98(1):152-159.
45.	Richardson SM, Knowles R, Tyler J, et al. Expression of glucose transporters GLUT-1, GLUT-3, GLUT-9 and HIF-1alpha in normal and degenerate human intervertebral disc. Histochem Cell Biol, 2008, 129(4):503-511.
46.	Fujita N, Imai J, Suzuki T, et al. Vascular endothelial growth factor-A is a survival factor for nucleus pulposus cells in the intervertebral disc. Biochem Biophys Res Commun, 2008, 372(2):367-372.
47.	Bibby SR, Urban JP. Effect of nutrient deprivation on the viability of intervertebral disc cells. Eur Spine J, 2004, 13(8):695-701.
48.	Horner HA, Urban JP. 2001 Volvo Award Winner in Basic Science Studies:Effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc. Spine (Phila Pa 1976), 2001, 26(23):2543-2549.
49.	Park JB, Chang H, Kim KW. Expression of Fas ligand and apoptosis of disc cells in herniated lumbar disc tissue. Spine (Phila Pa 1976), 2001, 26(6):618-621.
50.	Zeng Y, Danielson KG, Albert TJ, et al. HIF-1 alpha is a regulator of galectin-3 expression in the intervertebral disc. J Bone Miner Res, 2007, 22(12):1851-1861.
51.	Peng B, Hao J, Hou S, et al. Possible pathogenesis of painful intervertebral disc degeneration. Spine (Phila Pa 1976), 2006, 31(5):560-566.
52.	Risbud MV, Fertala J, Vresilovic EJ, et al. Nucleus pulposus cells upregulate PI3K/Akt and MEK/ERK signaling pathways under hypoxic conditions and resist apoptosis induced by serum withdrawal. Spine (Phila Pa 1976), 2005, 30(8):882-889.
53.	Risbud MV, Guttapalli A, Albert TJ, et al. Hypoxia activates MAPK activity in rat nucleus pulposus cells:regulation of integrin expression and cell survival. Spine (Phila Pa 1976), 2005, 30(22):2503-2509.
54.	Mazure NM, Pouysségur J. Hypoxia-induced autophagy:cell death or cell survival? Curr Opin Cell Biol, 2010, 22(2):177-180.
55.	Russell RC, Yuan HX, Guan KL. Autophagy regulation by nutrient signaling. Cell Res, 2014, 24(1):42-57.
56.	Galluzzi L, Pietrocola F, Levine B, et al. Metabolic control of autophagy. Cell, 2014, 159(6):1263-1276.
57.	Hu YL, DeLay M, Jahangiri A, et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res, 2012, 72(7):1773-1783.
58.	Srinivas V, Bohensky J, Zahm AM, et al. Autophagy in mineralizing tissues:microenvironmental perspectives. Cell Cycle, 2009, 8(3):391-393.
59.	Wu HM, Jiang ZF, Ding PS, et al. Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Sci Rep, 2015, 5:12291.
60.	Choi H, Merceron C, Mangiavini L, et al. Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling. Autophagy, 2016.[Epub ahead of print].
61.	Wang F, Cai F, Shi R, et al. Hypoxia regulates sumoylation pathways in intervertebral disc cells:implications for hypoxic adaptations. Osteoarthritis Cartilage, 2016, 24(6):1113-1124.
62.	Papandreou I, Cairns RA, Fontana L, et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab, 2006, 3(3):187-197.
63.	Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell, 2011, 9(4):298-310.
64.	Robins JC, Akeno N, Mukherjee A, et al. Hypoxia induces chondrocyte-specific gene expression in mesenchymal cells in association with transcriptional activation of Sox9. Bone, 2005, 37(3):313-322.
65.	Tran CM, Fujita N, Huang BL, et al. Hypoxia-inducible factor (HIF)-1alpha and CCN2 form a regulatory circuit in hypoxic nucleus pulposus cells:CCN2 suppresses HIF-1alpha level and transcriptional activity. J Biol Chem, 2013, 288(18):12654-12666.
66.	Li H, Liang CZ, Chen QX. Regulatory role of hypoxia inducible factor in the biological behavior of nucleus pulposus cells. Yonsei Med J, 2013, 54(4):807-812.
67.	Fujita N, Hirose Y, Tran CM, et al. HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. FASEB J, 2014, 28(6):2455-2465.
68.	Johnson ZJ, Gogate SS, Day R, et al. Aquaporin 1 and 5 expression decreases during human intervertebral disc degeneration Novel HIF-1-mediated regulation of aquaporins in NP cells. Oncotarget, 2015, 6(14):11945-11958.

1. Kadow T, Sowa G, Vo N, et al. Molecular basis of intervertebral disc degeneration and herniations:what are the important translational questions? Clin Orthop Relat Res, 2014, 473(6):1903-1912.
2. Phillips FM, An H, Kang JD, et al. Biologic treatment for intervertebral disc degeneration:summary statement. Spine (Phila Pa 1976), 2003, 28(15 Suppl):S99.
3. Maniadakis N, Gray A. The economic burden of back pain in the UK. Pain, 2000, 84(1):95-103.
4. Loenarz C, Coleman ML, Boleininger A, et al. The hypoxia-inducible transcription factor pathway regulates oxygen sensing in the simplest animal, Trichoplax adhaerens. EMBO Rep, 2011, 12(1):63-70.
5. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol, 1992, 12(12):5447-5454.
6. Zhao J, Zhang P, Qin L, et al. Hypoxia is essential for bone-tendon junction healing:the molecular biological evidence. Int Orthop, 2011, 35(6):925-928.
7. Fraisl P, Aragonés J, Carmeliet P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov, 2009, 8(2):139-152.
8. Lin WP, Wang XJ, Wang CR, et al. Polymorphism in the hypoxia-inducible factor 1alpha gene may confer susceptibility to LDD in Chinese cohort. PLoS One, 2013, 8(8):e73158.
9. Jiang BH, Semenza GL, Bauer C, et al. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol, 1996, 271(4 Pt 1):C1172-1180.
10. Huang LE, Gu J, Schau M, et al. Regulation of hypoxia-inducible factor 1alpha is mediated by an O₂-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A, 1998, 95(14):7987-7992.
11. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 2001, 107(1):43-54.
12. Kallio PJ, Wilson WJ, O'Brien S, et al. Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem, 1999, 274(10):6519-6525.
13. Masson N, Ratcliffe PJ. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels. J Cell Sci, 2003, 116(Pt 15):3041-3049.
14. Berra E, Benizri E, Ginouvès A, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J, 2003, 22(16):4082-4090.
15. Lando D, Peet DJ, Whelan DA, et al. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science, 2002, 295(5556):858-861.
16. Dunwoodie SL. The role of hypoxia in development of the Mammalian embryo. Dev Cell, 2009, 17(6):755-773.
17. Iyer NV, Kotch LE, Agani F, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev, 1998, 12(2):149-162.
18. Yoon D, Ponka P, Prchal JT. Hypoxia.5.Hypoxia and hematopoiesis. Am J Physiol Cell Physiol, 2011, 300(6):C1215-1222.
19. Schipani E, Ryan HE, Didrickson S, et al. Hypoxia in cartilage:HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev, 2001, 15(21):2865-2876.
20. Yun Z, Maecker HL, Johnson RS, et al. Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13:a mechanism for regulation of adipogenesis by hypoxia. Dev Cell, 2002, 2(3):331-341.
21. Kojima H, Gu H, Nomura S, et al. Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha-deficient chimeric mice. Proc Natl Acad Sci U S A, 2002, 99(4):2170-2174.
22. Dang EV, Barbi J, Yang HY, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell, 2011, 146(5):772-784.
23. Wang Y, Wan C, Deng L, et al. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest, 2007, 117(6):1616-1626.
24. Takubo K, Goda N, Yamada W, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell, 2010, 7(3):391-402.
25. Zinkernagel AS, Johnson RS, Nizet V. Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med (Berl), 2007, 85(12):1339-1346.
26. Gustafsson MV, Zheng X, Pereira T, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell, 2005, 9(5):617-628.
27. Shimoda LA, Manalo DJ, Sham JS, et al. Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. Am J Physiol Lung Cell Mol Physiol, 2001, 281(1):L202-208.
28. Yu AY, Shimoda LA, Iyer NV, et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J Clin Invest, 1999, 103(5):691-696.
29. Kline DD, Peng YJ, Manalo DJ, et al. Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. Proc Natl Acad Sci U S A, 2002, 99(2):821-826.
30. Genbacev O, Zhou Y, Ludlow JW, et al. Regulation of human placental development by oxygen tension. Science, 1997, 277(5332):1669-1672.
31. Scheid A, Wenger RH, Schäffer L, et al. Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3. FASEB J, 2002, 16(3):411-413.
32. Katz MM, Hargens AR, Garfin SR. Intervertebral disc nutrition. Diffusion versus convection. Clin Orthop Relat Res, 1986, (210):243-245.
33. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 2001, 294(5545):1337-1340.
34. Loinard C, Ginouves A, Vilar J, et al. Inhibition of prolyl hydroxylase domain proteins promotes therapeutic revascularization. Circulation, 2009, 120(1):50-59.
35. Hlatky MA, Quertermous T, Boothroyd DB, et al. Polymorphisms in hypoxia inducible factor 1 and the initial clinical presentation of coronary disease. Am Heart J, 2007, 154(6):1035-1042.
36. Resar JR, Roguin A, Voner J, et al. Hypoxia-inducible factor 1alpha polymorphism and coronary collaterals in patients with ischemic heart disease. Chest, 2005, 128(2):787-791.
37. Bosch-Marce M, Okuyama H, Wesley JB, et al. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res, 2007, 101(12):1310-1318.
38. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell, 2012, 148(3):399-408.
39. Merceron C, Mangiavini L, Robling A, et al. Loss of HIF-1α in the notochord results in cell death and complete disappearance of the nucleus pulposus. PLoS One, 2014, 9(10):e110768.
40. Agrawal A, Guttapalli A, Narayan S, et al. Normoxic stabilization of HIF-1alpha drives glycolytic metabolism and regulates aggrecan gene expression in nucleus pulposus cells of the rat intervertebral disk. Am J Physiol Cell Physiol, 2007, 293(2):C621-631.
41. Ha KY, Koh IJ, Kirpalani PA, et al. The expression of hypoxia inducible factor-1alpha and apoptosis in herniated discs. Spine (Phila Pa 1976), 2006, 31(12):1309-1313.
42. Agrawal A, Gajghate S, Smith H, et al. Cited2 modulates hypoxia-inducible factor-dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc. Arthritis Rheum, 2008, 58(12):3798-3808.
43. Rajpurohit R, Risbud MV, Ducheyne P, et al. Phenotypic characteristics of the nucleus pulposus:expression of hypoxia inducing factor-1, glucose transporter-1 and MMP-2. Cell Tissue Res, 2002, 308(3):401-407.
44. Risbud MV, Guttapalli A, Stokes DG, et al. Nucleus pulposus cells express HIF-1 alpha under normoxic culture conditions:a metabolic adaptation to the intervertebral disc microenvironment. J Cell Biochem, 2006, 98(1):152-159.
45. Richardson SM, Knowles R, Tyler J, et al. Expression of glucose transporters GLUT-1, GLUT-3, GLUT-9 and HIF-1alpha in normal and degenerate human intervertebral disc. Histochem Cell Biol, 2008, 129(4):503-511.
46. Fujita N, Imai J, Suzuki T, et al. Vascular endothelial growth factor-A is a survival factor for nucleus pulposus cells in the intervertebral disc. Biochem Biophys Res Commun, 2008, 372(2):367-372.
47. Bibby SR, Urban JP. Effect of nutrient deprivation on the viability of intervertebral disc cells. Eur Spine J, 2004, 13(8):695-701.
48. Horner HA, Urban JP. 2001 Volvo Award Winner in Basic Science Studies:Effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc. Spine (Phila Pa 1976), 2001, 26(23):2543-2549.
49. Park JB, Chang H, Kim KW. Expression of Fas ligand and apoptosis of disc cells in herniated lumbar disc tissue. Spine (Phila Pa 1976), 2001, 26(6):618-621.
50. Zeng Y, Danielson KG, Albert TJ, et al. HIF-1 alpha is a regulator of galectin-3 expression in the intervertebral disc. J Bone Miner Res, 2007, 22(12):1851-1861.
51. Peng B, Hao J, Hou S, et al. Possible pathogenesis of painful intervertebral disc degeneration. Spine (Phila Pa 1976), 2006, 31(5):560-566.
52. Risbud MV, Fertala J, Vresilovic EJ, et al. Nucleus pulposus cells upregulate PI3K/Akt and MEK/ERK signaling pathways under hypoxic conditions and resist apoptosis induced by serum withdrawal. Spine (Phila Pa 1976), 2005, 30(8):882-889.
53. Risbud MV, Guttapalli A, Albert TJ, et al. Hypoxia activates MAPK activity in rat nucleus pulposus cells:regulation of integrin expression and cell survival. Spine (Phila Pa 1976), 2005, 30(22):2503-2509.
54. Mazure NM, Pouysségur J. Hypoxia-induced autophagy:cell death or cell survival? Curr Opin Cell Biol, 2010, 22(2):177-180.
55. Russell RC, Yuan HX, Guan KL. Autophagy regulation by nutrient signaling. Cell Res, 2014, 24(1):42-57.
56. Galluzzi L, Pietrocola F, Levine B, et al. Metabolic control of autophagy. Cell, 2014, 159(6):1263-1276.
57. Hu YL, DeLay M, Jahangiri A, et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res, 2012, 72(7):1773-1783.
58. Srinivas V, Bohensky J, Zahm AM, et al. Autophagy in mineralizing tissues:microenvironmental perspectives. Cell Cycle, 2009, 8(3):391-393.
59. Wu HM, Jiang ZF, Ding PS, et al. Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Sci Rep, 2015, 5:12291.
60. Choi H, Merceron C, Mangiavini L, et al. Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling. Autophagy, 2016.[Epub ahead of print].
61. Wang F, Cai F, Shi R, et al. Hypoxia regulates sumoylation pathways in intervertebral disc cells:implications for hypoxic adaptations. Osteoarthritis Cartilage, 2016, 24(6):1113-1124.
62. Papandreou I, Cairns RA, Fontana L, et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab, 2006, 3(3):187-197.
63. Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell, 2011, 9(4):298-310.
64. Robins JC, Akeno N, Mukherjee A, et al. Hypoxia induces chondrocyte-specific gene expression in mesenchymal cells in association with transcriptional activation of Sox9. Bone, 2005, 37(3):313-322.
65. Tran CM, Fujita N, Huang BL, et al. Hypoxia-inducible factor (HIF)-1alpha and CCN2 form a regulatory circuit in hypoxic nucleus pulposus cells:CCN2 suppresses HIF-1alpha level and transcriptional activity. J Biol Chem, 2013, 288(18):12654-12666.
66. Li H, Liang CZ, Chen QX. Regulatory role of hypoxia inducible factor in the biological behavior of nucleus pulposus cells. Yonsei Med J, 2013, 54(4):807-812.
67. Fujita N, Hirose Y, Tran CM, et al. HIF-1-PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells. FASEB J, 2014, 28(6):2455-2465.
68. Johnson ZJ, Gogate SS, Day R, et al. Aquaporin 1 and 5 expression decreases during human intervertebral disc degeneration Novel HIF-1-mediated regulation of aquaporins in NP cells. Oncotarget, 2015, 6(14):11945-11958.

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Chinese Journal of Reparative and Reconstructive Surgery

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