Yonsei Med J.  2013 Jul;54(4):807-812. 10.3349/ymj.2013.54.4.807.

Regulatory Role of Hypoxia Inducible Factor in the Biological Behavior of Nucleus Pulposus Cells

Affiliations
  • 1Department of Orthopedics Surgery, The Second Hospital of Medical College, Zhejiang University, Hangzhou, China. zrcqx@zju.edu.cn

Abstract

Intervertebral disc (IVD) degeneration is implicated as a major cause of low back pain. The alternated phenotypes, reduced cell survival, decreased metabolic activity, loss of matrix production and dystrophic mineralization of nucleus pulposus (NP) cells may be key contributors to progressive IVD degeneration. IVD is the largest avascular structure in the body, characterized by low oxygen tension in vivo. Hypoxia-inducible factor (HIF) is a master transcription factor that is induced upon hypoxia and directs coordinated cellular responses to hypoxic environments. This review summarizes relevant studies concerning the involvement of HIF in the regulation of biological behaviors of NP cells. We describe current data on the expression of HIF in NP cells and further discuss the various roles that HIF plays in the regulation of the phenotype, survival, metabolism, matrix production and dystrophic mineralization of NP cells. Here, we conclude that HIF may be a promising target for the prevention and treatment of IVD degeneration.

Keyword

Hypoxia inducible factor; intervertebral disc degeneration; nucleus pulposus

MeSH Terms

Animals
Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism
Cell Survival
Extracellular Matrix/metabolism
Humans
Hypoxia-Inducible Factor 1/genetics/*metabolism
Intervertebral Disc/*cytology/metabolism
Intervertebral Disc Degeneration/*metabolism/*pathology
Basic Helix-Loop-Helix Transcription Factors
Hypoxia-Inducible Factor 1

Cited by  1 articles

Hypoxia Induces Epithelial-Mesenchymal Transition in Follicular Thyroid Cancer: Involvement of Regulation of Twist by Hypoxia Inducible Factor-1α
Yeon Ju Yang, Hwi Jung Na, Michelle J. Suh, Myung Jin Ban, Hyung Kwon Byeon, Won Shik Kim, Jae Wook Kim, Eun Chang Choi, Hyeong Ju Kwon, Jae Won Chang, Yoon Woo Koh
Yonsei Med J. 2015;56(6):1503-1514.    doi: 10.3349/ymj.2015.56.6.1503.


Reference

1. Apeldoorn AT, Bosmans JE, Ostelo RW, de Vet HC, van Tulder MW. Cost-effectiveness of a classification-based system for sub-acute and chronic low back pain. Eur Spine J. 2012; 21:1290–1300. PMID: 22258622.
Article
2. Lin CW, Haas M, Maher CG, Machado LA, van Tulder MW. Cost-effectiveness of guideline-endorsed treatments for low back pain: a systematic review. Eur Spine J. 2011; 20:1024–1038. PMID: 21229367.
Article
3. Ohtori S, Inoue G, Orita S, Eguchi Y, Ochiai N, Kishida S, et al. Transdermal fentanyl for chronic low back pain. Yonsei Med J. 2012; 53:788–793. PMID: 22665347.
Article
4. Oksuz E. Prevalence, risk factors, and preference-based health states of low back pain in a Turkish population. Spine (Phila Pa 1976). 2006; 31:E968–E972. PMID: 17139213.
Article
5. Ciapetti G, Granchi D, Devescovi V, Leonardi E, Greggi T, Di Silvestre M, et al. Ex vivo observation of human intervertebral disc tissue and cells isolated from degenerated intervertebral discs. Eur Spine J. 2012; 21(Suppl 1):S10–S19. PMID: 22395304.
Article
6. Park MS, Lee HM, Hahn SB, Moon SH, Kim YT, Lee CS, et al. The association of the activation-inducible tumor necrosis factor receptor and ligand with lumbar disc herniation. Yonsei Med J. 2007; 48:839–846. PMID: 17963343.
Article
7. Roberts S. Disc morphology in health and disease. Biochem Soc Trans. 2002; 30(Pt 6):864–869. PMID: 12440934.
Article
8. Chen CS, Cheng CK, Liu CL, Lo WH. Stress analysis of the disc adjacent to interbody fusion in lumbar spine. Med Eng Phys. 2001; 23:483–491. PMID: 11574255.
Article
9. Stemple DL. Structure and function of the notochord: an essential organ for chordate development. Development. 2005; 132:2503–2512. PMID: 15890825.
Article
10. Rajpurohit R, Risbud MV, Ducheyne P, Vresilovic EJ, Shapiro IM. Phenotypic characteristics of the nucleus pulposus: expression of hypoxia inducing factor-1, glucose transporter-1 and MMP-2. Cell Tissue Res. 2002; 308:401–407. PMID: 12107433.
Article
11. Yang X, Li X. Nucleus pulposus tissue engineering: a brief review. Eur Spine J. 2009; 18:1564–1572. PMID: 19603198.
Article
12. Costa F, Sassi M, Ortolina A, Cardia A, Assietti R, Zerbi A, et al. Stand-alone cage for posterior lumbar interbody fusion in the treatment of high-degree degenerative disc disease: design of a new device for an "old" technique. A prospective study on a series of 116 patients. Eur Spine J. 2011; 20(Suppl 1):S46–S56. PMID: 21404031.
Article
13. Taylor JR. Growth of human intervertebral discs and vertebral bodies. J Anat. 1975; 120(Pt 1):49–68. PMID: 1184458.
14. Rudert M, Tillmann B. Lymph and blood supply of the human intervertebral disc. Cadaver study of correlations to discitis. Acta Orthop Scand. 1993; 64:37–40. PMID: 8451943.
Article
15. Fujita N, Markova D, Anderson DG, Chiba K, Toyama Y, Shapiro IM, 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. J Biol Chem. 2012; 287:16975–16986. PMID: 22451659.
16. Urban JP. The role of the physicochemical environment in determining disc cell behaviour. Biochem Soc Trans. 2002; 30(Pt 6):858–864. PMID: 12440933.
Article
17. Urban JP, Smith S, Fairbank JC. Nutrition of the intervertebral disc. Spine (Phila Pa 1976). 2004; 29:2700–2709. PMID: 15564919.
Article
18. Richardson SM, Knowles R, Tyler J, Mobasheri A, Hoyland JA. Expression of glucose transporters GLUT-1, GLUT-3, GLUT-9 and HIF-1alpha in normal and degenerate human intervertebral disc. Histochem Cell Biol. 2008; 129:503–511. PMID: 18172662.
19. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998; 394:485–490. PMID: 9697772.
20. Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med. 2001; 7:345–350. PMID: 11516994.
Article
21. Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 2000; 88:1474–1480. PMID: 10749844.
Article
22. 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; 12:5447–5454. PMID: 1448077.
Article
23. Zhao J, Zhang P, Qin L, Pan XH. Hypoxia is essential for bone-tendon junction healing: the molecular biological evidence. Int Orthop. 2011; 35:925–928. PMID: 21127862.
Article
24. Risbud MV, Guttapalli A, Stokes DG, Hawkins D, Danielson KG, Schaer TP, 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; 98:152–159. PMID: 16408279.
25. Agrawal A, Gajghate S, Smith H, Anderson DG, Albert TJ, Shapiro IM, 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; 58:3798–3808. PMID: 19035510.
Article
26. Fujita N, Chiba K, Shapiro IM, Risbud MV. HIF-1α and HIF-2α degradation is differentially regulated in nucleus pulposus cells of the intervertebral disc. J Bone Miner Res. 2012; 27:401–412. PMID: 21987385.
Article
27. Zeng Y, Danielson KG, Albert TJ, Shapiro IM, Risbud MV. HIF-1 alpha is a regulator of galectin-3 expression in the intervertebral disc. J Bone Miner Res. 2007; 22:1851–1861. PMID: 17592963.
28. Ha KY, Koh IJ, Kirpalani PA, Kim YY, Cho YK, Khang GS, et al. The expression of hypoxia inducible factor-1alpha and apoptosis in herniated discs. Spine (Phila Pa 1976). 2006; 31:1309–1313. PMID: 16721291.
29. Agrawal A, Guttapalli A, Narayan S, Albert TJ, Shapiro IM, Risbud MV. 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:C621–C631. PMID: 17442734.
30. Gogate SS, Nasser R, Shapiro IM, Risbud MV. Hypoxic regulation of β-1,3-glucuronyltransferase 1 expression in nucleus pulposus cells of the rat intervertebral disc: role of hypoxia-inducible factor proteins. Arthritis Rheum. 2011; 63:1950–1960. PMID: 21400481.
Article
31. Skubutyte R, Markova D, Freeman TA, Anderson DG, Dion AS, Williams CJ, et al. Hypoxia-inducible factor regulation of ANK expression in nucleus pulposus cells: possible implications in controlling dystrophic mineralization in the intervertebral disc. Arthritis Rheum. 2010; 62:2707–2715. PMID: 20496369.
Article
32. Obach M, Navarro-Sabaté A, Caro J, Kong X, Duran J, Gómez M, et al. 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia. J Biol Chem. 2004; 279:53562–53570. PMID: 15466858.
Article
33. Brahimi-Horn C, Berra E, Pouysségur J. Hypoxia: the tumor's gateway to progression along the angiogenic pathway. Trends Cell Biol. 2001; 11:S32–S36. PMID: 11684440.
Article
34. Boskey AL. Signaling in response to hypoxia and normoxia in the intervertebral disc. Arthritis Rheum. 2008; 58:3637–3639. PMID: 19035504.
Article
35. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002; 64:993–998. PMID: 12213597.
Article
36. Kaufman B, Scharf O, Arbeit J, Ashcroft M, Brown JM, Bruick RK, et al. Proceedings of the Oxygen Homeostasis/Hypoxia Meeting. Cancer Res. 2004; 64:3350–3356. PMID: 15126380.
37. Risbud MV, Schipani E, Shapiro IM. Hypoxic regulation of nucleus pulposus cell survival: from niche to notch. Am J Pathol. 2010; 176:1577–1583. PMID: 20133815.
38. Takeda K, Fong GH. Prolyl hydroxylase domain 2 protein suppresses hypoxia-induced endothelial cell proliferation. Hypertension. 2007; 49:178–184. PMID: 17101841.
Article
39. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004; 279:38458–38465. PMID: 15247232.
Article
40. Fujita N, Imai J, Suzuki T, Yamada M, Ninomiya K, Miyamoto K, et al. Vascular endothelial growth factor-A is a survival factor for nucleus pulposus cells in the intervertebral disc. Biochem Biophys Res Commun. 2008; 372:367–372. PMID: 18492486.
Article
41. Bibby SR, Urban JP. Effect of nutrient deprivation on the viability of intervertebral disc cells. Eur Spine J. 2004; 13:695–701. PMID: 15048560.
Article
42. 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; 26:2543–2549. PMID: 11725234.
Article
43. 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; 26:618–621. PMID: 11246372.
Article
44. Hsu DK, Yang RY, Pan Z, Yu L, Salomon DR, Fung-Leung WP, et al. Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. Am J Pathol. 2000; 156:1073–1083. PMID: 10702423.
Article
45. Takahashi S. Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull. 2011; 34:1785–1788. PMID: 22130231.
Article
46. Malandrino A, Noailly J, Lacroix D. The effect of sustained compression on oxygen metabolic transport in the intervertebral disc decreases with degenerative changes. PLoS Comput Biol. 2011; 7:e1002112. PMID: 21829341.
Article
47. Holm S, Maroudas A, Urban JP, Selstam G, Nachemson A. Nutrition of the intervertebral disc: solute transport and metabolism. Connect Tissue Res. 1981; 8:101–119. PMID: 6453689.
Article
48. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994; 269:23757–23763. PMID: 8089148.
Article
49. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006; 3:187–197. PMID: 16517406.
Article
50. Vannucci SJ, Reinhart R, Maher F, Bondy CA, Lee WH, Vannucci RC, et al. Alterations in GLUT1 and GLUT3 glucose transporter gene expression following unilateral hypoxia-ischemia in the immature rat brain. Brain Res Dev Brain Res. 1998; 107:255–264.
Article
51. Bell GI, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, et al. Molecular biology of mammalian glucose transporters. Diabetes Care. 1990; 13:198–208. PMID: 2407475.
Article
52. Joost HG, Bell GI, Best JD, Birnbaum MJ, Charron MJ, Chen YT, et al. Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol Endocrinol Metab. 2002; 282:E974–E976. PMID: 11882521.
53. Bibby SR, Jones DA, Lee RB, Yu J, Urban JPG. The pathophysiology of the intervertebral disc. Joint Bone Spine. 2001; 68:537–542. PMID: 11808995.
Article
54. Bruehlmann SB, Rattner JB, Matyas JR, Duncan NA. Regional variations in the cellular matrix of the annulus fibrosus of the intervertebral disc. J Anat. 2002; 201:159–171. PMID: 12220124.
Article
55. Le Maitre CL, Freemont AJ, Hoyland JA. Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc. J Pathol. 2004; 204:47–54. PMID: 15307137.
Article
56. Le Maitre CL, Pockert A, Buttle DJ, Freemont AJ, Hoyland JA. Matrix synthesis and degradation in human intervertebral disc degeneration. Biochem Soc Trans. 2007; 35(Pt 4):652–655. PMID: 17635113.
57. Boxberger JI, Sen S, Yerramalli CS, Elliott DM. Nucleus pulposus glycosaminoglycan content is correlated with axial mechanics in rat lumbar motion segments. J Orthop Res. 2006; 24:1906–1915. PMID: 16865712.
Article
58. Kirsch T. Determinants of pathological mineralization. Curr Opin Rheumatol. 2006; 18:174–180. PMID: 16462525.
Article
59. Golub EE. Biomineralization and matrix vesicles in biology and pathology. Semin Immunopathol. 2011; 33:409–417. PMID: 21140263.
Article
60. Melrose J, Burkhardt D, Taylor TK, Dillon CT, Read R, Cake M, et al. Calcification in the ovine intervertebral disc: a model of hydroxyapatite deposition disease. Eur Spine J. 2009; 18:479–489. PMID: 19165512.
Article
61. Giachelli CM. Ectopic calcification: gathering hard facts about soft tissue mineralization. Am J Pathol. 1999; 154:671–675. PMID: 10079244.
62. Gurley KA, Chen H, Guenther C, Nguyen ET, Rountree RB, Schoor M, et al. Mineral formation in joints caused by complete or joint-specific loss of ANK function. J Bone Miner Res. 2006; 21:1238–1247. PMID: 16869722.
Article
63. Zaka R, Williams CJ. Role of the progressive ankylosis gene in cartilage mineralization. Curr Opin Rheumatol. 2006; 18:181–186. PMID: 16462526.
Article
64. Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M, et al. Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet. 2002; 71:933–940. PMID: 12297987.
Article
65. Williams CJ, Pendleton A, Bonavita G, Reginato AJ, Hughes AE, Peariso S, et al. Mutations in the amino terminus of ANKH in two US families with calcium pyrophosphate dihydrate crystal deposition disease. Arthritis Rheum. 2003; 48:2627–2631. PMID: 13130483.
Article
Full Text Links
  • YMJ
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr