血紅素氧化酶1在骨組織工程中的應用分析研究進展_《中國修復重建外科雜志》

作者：

陳曉鵬 ^1,2 , 胡永成 ² , 方成 ^1,2 , 張榮信 ¹ , 王晗 ^1,2 , 何鑫 ^1,2 , 袁斌斌 ^1,2

1天津醫科大學研究生院（天津，300070）;;
2天津醫院骨與軟組織腫瘤科;

關鍵詞：

血紅素氧化酶1 生長因子骨組織工程

DOI：

10.7507/1002-1892.20130274

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目的綜述血紅素氧化酶1（heme oxygenase 1，HO-1）的研究進展，全面了解HO-1的各種作用及其對干細胞成骨、成血管的影響，分析其在骨組織工程中的應用。方法廣泛查閱近年來國內外有關HO-1的相關文獻，并綜合分析。結果HO-1及其代謝產物不但具有抗炎、抗凋亡和細胞保護作用，而且還可以協調多種因子促進血管生成及對已經存在的血管發揮保護作用。此外，HO-1對干細胞增殖、旁分泌、分化和凋亡有一定影響。結論HO-1可作為一種多功能的生長因子應用于骨組織工程，但尚需研究各種功能是否具有協同效應，以更好地促進骨修復。

引用本文： 陳曉鵬,胡永成,方成,張榮信,王晗,何鑫,袁斌斌. 血紅素氧化酶1在骨組織工程中的應用分析研究進展. 中國修復重建外科雜志, 2013, 27(10): 1256-1261. doi: 10.7507/1002-1892.20130274 復制

1.	Evans CH. Gene delivery to bone. Advanced Drug Delivery Reviews, 2012, 64(12): 1331-1340.
2.	劉顯挺, 江潞, 曾昕, 等. 調控VEGF的轉錄因子及其與腫瘤的關系. 中國腫瘤生物治療雜志, 2010, 17(4): 468-472.
3.	Kim YM, Pae HO, Park JE, et al. Heme oxygenase in the regulation of vascular biology: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal, 2011, 14(1): 137-167.
4.	Zarjou A, Kim J, Traylor AM, et al. Paracrine effects of mesenchymal stem cells in cisplatin-induced renal injury require heme oxygenase-1. Am J Physiol Renal Physiol, 2011, 300(1): F254-262.
5.	Jang HJ, Tsoyi K, Kim YM, et al. (S)-1-alpha-naphthylmethyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (CKD712), promotes wound closure by producing VEGF through HO-1 induction in human dermal fibroblasts and mouse skin. Br J Pharmacol, 2013, 168(6): 1485-1496.
6.	Loboda A, Jazwa A, Grochot-Przeczek A, et al. Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal, 2008, 10(10): 1767-1812.
7.	Tesfay L, Huhn AJ, Hatcher H, et al. Ferritin blocks inhibitory effects of two-chain high molecular weight kininogen (HKa) on adhesion and survival signaling in endothelial cells. PLoS One, 2012, 7(7): e40030.
8.	Choi YK, Kim CK, Lee H, et al. Carbon monoxide promotes VEGF expression by increasing HIF-1alpha protein level via two distinct mechanisms, translational activation and stabilization of HIF-1alpha protein. J Biol Chem, 2010, 285(42): 32116-32125.
9.	Liu XM, Peyton KJ, Durante W. Physiological cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1. Am J Physiol Heart Circ Physiol, 2013, 304(12): H1634-1643.
10.	Shakeri-Manesch S, Zeyda M, Huber J, et al. Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance. Int J Obes (Lond), 2009, 33(11): 1257-1264.
11.	Zou YY, Kan EM, Lu J, et al. Primary blast injury-induced lesions in the retina of adult rats. J Neuroinflammation, 2013, 10: 79.
12.	Wu ML, Ho YC, Yet SF. A central role of heme oxygenase-1 in cardiovascular protection. Antioxid Redox Signal, 2011, 15(7): 1835-1846.
13.	Tenhunen R, Marver HS, Schmid R. The enzymatic catabolism of hemoglobin: stimulation of microsomal heme oxygenase by hemin. J Lab Clin Med, 1970, 75(3): 410-421.
14.	Gabunia K, Ellison SP, Singh H, et al. Interleukin-19 (IL-19) induces heme oxygenase-1 (HO-1) expression and decreases reactive oxygen species in human vascular smooth muscle cells. J Biol Chem, 2012, 287(4): 2477-2484.
15.	Grochot-Przeczek A, Dulak J, Jozkowicz A. Haem oxygenase-1: non-canonical roles in physiology and pathology. Clin Sci (Lond), 2012, 122(3): 93-103.
16.	Kahlo K, Fill Malfertheiner S, Ignatov T, et al. HO-1 as modulator of the innate immune response in pregnancy. Am J Reprod Immunol, 2013, 70(1): 24-30.
17.	An L, Liu CT, Yu MJ, et al. Heme oxygenase-1 system, inflammation and ventilator-induced lung injury. Eur J Pharmacol, 2012, 677(1-3): 1-4.
18.	Otterbein LE, Zuckerbraun BS, Haga M, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med, 2003, 9(2): 183-190.
19.	Sarady JK, Zuckerbraun BS, Bilban M, et al. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J, 2004, 18(7): 854-856.
20.	Mancuso C, Barone E. The heme oxygenase/biliverdin reductase pathway in drug research and development. Curr Drug Metab, 2009, 10(6): 579-594.
21.	Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci U S A, 1998, 95(26): 15809-15814.
22.	Giavazzi R, Sennino B, Coltrini D, et al. Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol, 2003, 162(6): 1913-1926.
23.	Deshane J, Chen S, Caballero S, et al. Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med, 2007, 204(3): 605-618.
24.	Hiasa K, Ishibashi M, Ohtani K, et al. Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization. Circulation, 2004, 109(20): 2454-2461.
25.	Lin HH, Chen YH, Yet SF, et al. After vascular injury, heme oxygenase-1/carbon monoxide enhances re-endothelialization via promoting mobilization of circulating endothelial progenitor cells. J Thromb Haemost, 2009, 7(8): 1401-1408.
26.	Jozkowicz A, Cooke JP, Guevara I, et al. Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF. Cardiovasc Res, 2001, 51(4): 773-783.
27.	Marazioti A, Bucci M, Coletta C, et al. Inhibition of nitric oxide-stimulated vasorelaxation by carbon monoxide-releasing molecules. Arterioscler Thromb Vasc Biol, 2011, 31(11): 2570-2576.
28.	He M, Siow RC, Sugden D, et al. Induction of HO-1 and redox signaling in endothelial cells by advanced glycation end products: a role for Nrf2 in vascular protection in diabetes. Nutr Metab Cardiovasc Dis, 2011, 21(4): 277-285.
29.	Wu KC, Mcdonald PR, Liu JJ, et al. Implementation of a high-throughput screen for identifying small molecules to activate the Keap1-Nrf2-ARE pathway. PLoS One, 2012, 7(10): e44686.
30.	Ferrando M, Gueron G, Elguero B, et al. Heme oxygenase 1 (HO- 1) challenges the angiogenic switch in prostate cancer. Angiogenesis, 2011, 14(4): 467-479.
31.	Guleng B, Tateishi K, Ohta M, et al. Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res, 2005, 65(13): 5864-5871.
32.	徐衛華, 沈振亞. 慢病毒介導HO-1基因轉染豬骨髓間充質干細胞的表達. 江蘇醫藥, 2012, 38(15): 1750-1753.
33.	Hou C, Shen L, Huang Q, et al. The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer. Biomaterials, 2013, 34(1): 112-120.
34.	Salgado AJ, Reis RL, Sousa NJ, et al. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther, 2010, 5(2): 103-110.
35.	Zuk P. Adipose-derived stem cells in tissue regeneration: a review. ISRN Stem Cells, 2013: 35.
36.	Doorn J, Moll G, Le Blanc K, et al. Therapeutic applications of mesenchymal stromal cells: paracrine effects and potential improvements. Tissue Eng Part B Rev, 2012, 18(2): 101-115.
37.	Stagg J, Galipeau J. Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. Curr Mol Med, 2013, 13(5): 856-867.
38.	Mougiakakos D, Jitschin R, Johansson CC, et al. The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. Blood, 2011, 117(18): 4826-4835.
39.	Vanella L, Kim DH, Asprinio D, et al. HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage. Bone, 2010, 46(1): 236-243.
40.	Vanella L, Sodhi K, Kim DH, et al. Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade. Stem Cell Res Ther, 2013, 4(2): 28.
41.	Zwerina J, Tzima S, Hayer S, et al. Heme oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption. FASEB J, 2005, 19(14): 2011-2013.
42.	Lin TH, Tang CH, Hung SY, et al. Upregulation of heme oxygenase-1 inhibits the maturation and mineralization of osteoblasts. J Cell Physiol, 2010, 222(3): 757-768.
43.	Yang JJ, Yang X, Liu ZQ, et al. Transplantation of adipose tissue-derived stem cells overexpressing heme oxygenase-1 improves functions and remodeling of infarcted myocardium in rabbits. Tohoku J Exp Med, 2012, 226(3): 231-241.
44.	陳學忠, 李志宏, 郭勇, 等. 大段組織工程骨的構建策略及存在的問題. 中華骨科雜志, 2011, 31(7): 811-814.
45.	樓曉莉, 陳江萍, 宋建星. 腺病毒介導VEGF和HO-1聯合治療缺血隨意皮瓣的實驗研究. 中國美容整形外科雜志, 2011, 22(6): 381-384.
46.	Jazwa A, Stepniewski J, Zamykal M, et al. Pre-emptive hypoxia-regulated HO-1 gene therapy improves post-ischaemic limb perfusion and tissue regeneration in mice. Cardiovasc Res, 2013, 97(1): 115-124.
47.	Chung J, Shin DY, Zheng M, et al. Carbon monoxide, a reaction product of heme oxygenase-1, suppresses the expression of C-reactive protein by endoplasmic reticulum stress through modulation of the unfolded protein response. Mol Immunol, 2011, 48(15-16): 1793-1799.

1. Evans CH. Gene delivery to bone. Advanced Drug Delivery Reviews, 2012, 64(12): 1331-1340.
2. 劉顯挺, 江潞, 曾昕, 等. 調控VEGF的轉錄因子及其與腫瘤的關系. 中國腫瘤生物治療雜志, 2010, 17(4): 468-472.
3. Kim YM, Pae HO, Park JE, et al. Heme oxygenase in the regulation of vascular biology: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal, 2011, 14(1): 137-167.
4. Zarjou A, Kim J, Traylor AM, et al. Paracrine effects of mesenchymal stem cells in cisplatin-induced renal injury require heme oxygenase-1. Am J Physiol Renal Physiol, 2011, 300(1): F254-262.
5. Jang HJ, Tsoyi K, Kim YM, et al. (S)-1-alpha-naphthylmethyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (CKD712), promotes wound closure by producing VEGF through HO-1 induction in human dermal fibroblasts and mouse skin. Br J Pharmacol, 2013, 168(6): 1485-1496.
6. Loboda A, Jazwa A, Grochot-Przeczek A, et al. Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal, 2008, 10(10): 1767-1812.
7. Tesfay L, Huhn AJ, Hatcher H, et al. Ferritin blocks inhibitory effects of two-chain high molecular weight kininogen (HKa) on adhesion and survival signaling in endothelial cells. PLoS One, 2012, 7(7): e40030.
8. Choi YK, Kim CK, Lee H, et al. Carbon monoxide promotes VEGF expression by increasing HIF-1alpha protein level via two distinct mechanisms, translational activation and stabilization of HIF-1alpha protein. J Biol Chem, 2010, 285(42): 32116-32125.
9. Liu XM, Peyton KJ, Durante W. Physiological cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1. Am J Physiol Heart Circ Physiol, 2013, 304(12): H1634-1643.
10. Shakeri-Manesch S, Zeyda M, Huber J, et al. Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance. Int J Obes (Lond), 2009, 33(11): 1257-1264.
11. Zou YY, Kan EM, Lu J, et al. Primary blast injury-induced lesions in the retina of adult rats. J Neuroinflammation, 2013, 10: 79.
12. Wu ML, Ho YC, Yet SF. A central role of heme oxygenase-1 in cardiovascular protection. Antioxid Redox Signal, 2011, 15(7): 1835-1846.
13. Tenhunen R, Marver HS, Schmid R. The enzymatic catabolism of hemoglobin: stimulation of microsomal heme oxygenase by hemin. J Lab Clin Med, 1970, 75(3): 410-421.
14. Gabunia K, Ellison SP, Singh H, et al. Interleukin-19 (IL-19) induces heme oxygenase-1 (HO-1) expression and decreases reactive oxygen species in human vascular smooth muscle cells. J Biol Chem, 2012, 287(4): 2477-2484.
15. Grochot-Przeczek A, Dulak J, Jozkowicz A. Haem oxygenase-1: non-canonical roles in physiology and pathology. Clin Sci (Lond), 2012, 122(3): 93-103.
16. Kahlo K, Fill Malfertheiner S, Ignatov T, et al. HO-1 as modulator of the innate immune response in pregnancy. Am J Reprod Immunol, 2013, 70(1): 24-30.
17. An L, Liu CT, Yu MJ, et al. Heme oxygenase-1 system, inflammation and ventilator-induced lung injury. Eur J Pharmacol, 2012, 677(1-3): 1-4.
18. Otterbein LE, Zuckerbraun BS, Haga M, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med, 2003, 9(2): 183-190.
19. Sarady JK, Zuckerbraun BS, Bilban M, et al. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J, 2004, 18(7): 854-856.
20. Mancuso C, Barone E. The heme oxygenase/biliverdin reductase pathway in drug research and development. Curr Drug Metab, 2009, 10(6): 579-594.
21. Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci U S A, 1998, 95(26): 15809-15814.
22. Giavazzi R, Sennino B, Coltrini D, et al. Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol, 2003, 162(6): 1913-1926.
23. Deshane J, Chen S, Caballero S, et al. Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med, 2007, 204(3): 605-618.
24. Hiasa K, Ishibashi M, Ohtani K, et al. Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization. Circulation, 2004, 109(20): 2454-2461.
25. Lin HH, Chen YH, Yet SF, et al. After vascular injury, heme oxygenase-1/carbon monoxide enhances re-endothelialization via promoting mobilization of circulating endothelial progenitor cells. J Thromb Haemost, 2009, 7(8): 1401-1408.
26. Jozkowicz A, Cooke JP, Guevara I, et al. Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF. Cardiovasc Res, 2001, 51(4): 773-783.
27. Marazioti A, Bucci M, Coletta C, et al. Inhibition of nitric oxide-stimulated vasorelaxation by carbon monoxide-releasing molecules. Arterioscler Thromb Vasc Biol, 2011, 31(11): 2570-2576.
28. He M, Siow RC, Sugden D, et al. Induction of HO-1 and redox signaling in endothelial cells by advanced glycation end products: a role for Nrf2 in vascular protection in diabetes. Nutr Metab Cardiovasc Dis, 2011, 21(4): 277-285.
29. Wu KC, Mcdonald PR, Liu JJ, et al. Implementation of a high-throughput screen for identifying small molecules to activate the Keap1-Nrf2-ARE pathway. PLoS One, 2012, 7(10): e44686.
30. Ferrando M, Gueron G, Elguero B, et al. Heme oxygenase 1 (HO- 1) challenges the angiogenic switch in prostate cancer. Angiogenesis, 2011, 14(4): 467-479.
31. Guleng B, Tateishi K, Ohta M, et al. Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res, 2005, 65(13): 5864-5871.
32. 徐衛華, 沈振亞. 慢病毒介導HO-1基因轉染豬骨髓間充質干細胞的表達. 江蘇醫藥, 2012, 38(15): 1750-1753.
33. Hou C, Shen L, Huang Q, et al. The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer. Biomaterials, 2013, 34(1): 112-120.
34. Salgado AJ, Reis RL, Sousa NJ, et al. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther, 2010, 5(2): 103-110.
35. Zuk P. Adipose-derived stem cells in tissue regeneration: a review. ISRN Stem Cells, 2013: 35.
36. Doorn J, Moll G, Le Blanc K, et al. Therapeutic applications of mesenchymal stromal cells: paracrine effects and potential improvements. Tissue Eng Part B Rev, 2012, 18(2): 101-115.
37. Stagg J, Galipeau J. Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. Curr Mol Med, 2013, 13(5): 856-867.
38. Mougiakakos D, Jitschin R, Johansson CC, et al. The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. Blood, 2011, 117(18): 4826-4835.
39. Vanella L, Kim DH, Asprinio D, et al. HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage. Bone, 2010, 46(1): 236-243.
40. Vanella L, Sodhi K, Kim DH, et al. Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade. Stem Cell Res Ther, 2013, 4(2): 28.
41. Zwerina J, Tzima S, Hayer S, et al. Heme oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption. FASEB J, 2005, 19(14): 2011-2013.
42. Lin TH, Tang CH, Hung SY, et al. Upregulation of heme oxygenase-1 inhibits the maturation and mineralization of osteoblasts. J Cell Physiol, 2010, 222(3): 757-768.
43. Yang JJ, Yang X, Liu ZQ, et al. Transplantation of adipose tissue-derived stem cells overexpressing heme oxygenase-1 improves functions and remodeling of infarcted myocardium in rabbits. Tohoku J Exp Med, 2012, 226(3): 231-241.
44. 陳學忠, 李志宏, 郭勇, 等. 大段組織工程骨的構建策略及存在的問題. 中華骨科雜志, 2011, 31(7): 811-814.
45. 樓曉莉, 陳江萍, 宋建星. 腺病毒介導VEGF和HO-1聯合治療缺血隨意皮瓣的實驗研究. 中國美容整形外科雜志, 2011, 22(6): 381-384.
46. Jazwa A, Stepniewski J, Zamykal M, et al. Pre-emptive hypoxia-regulated HO-1 gene therapy improves post-ischaemic limb perfusion and tissue regeneration in mice. Cardiovasc Res, 2013, 97(1): 115-124.
47. Chung J, Shin DY, Zheng M, et al. Carbon monoxide, a reaction product of heme oxygenase-1, suppresses the expression of C-reactive protein by endoplasmic reticulum stress through modulation of the unfolded protein response. Mol Immunol, 2011, 48(15-16): 1793-1799.

《中國修復重建外科雜志》

血紅素氧化酶1在骨組織工程中的應用分析研究進展

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血紅素氧化酶1在骨組織工程中的應用分析研究進展

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