Research progress of P75 neurotrophin receptor and new idea of nonunion treatment_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LI Jiayong , WANG Ming , PENG Chengfei ,  BEI Chaoyong

Department of Limb Trauma, Affiliated Hospital of Guilin Medical College, Guilin Guangxi, 541001, P.R.China;

Corresponding author：

BEI Chaoyong, Email: beichy2008@126.com

Keywords：

P75 neurotrophin receptor; nonunion; angiogenesis

DOI：

10.7507/1002-1892.201609008

Video：

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Objective To review the research progress of P75 neurotrophin receptor (P75NTR) so as to clarify its mechanism, and to explore its relationship with nonunion so as to provide a new idea for the treatment of nonunion. Methods The related domestic and foreign literature of P75NTR in recent years was extensively reviewed, summarized, and analyzed to find out the mechanism of action of P75NTR and the pathological factors of nonunion formation. Results P75NTR can express in nonunion tissues and lead to defect of fibrin degradation and inhibition of angiogenesis, which play an important role in the pathogenesis of nonunion. Conclusion It needs to be confirmed by further study whether the purpose of treating nonunion can be achieved by blocking the effects described above of P75NTR.

Citation： LIJiayong, WANGMing, PENGChengfei, BEIChaoyong. Research progress of P75 neurotrophin receptor and new idea of nonunion treatment. Chinese Journal of Reparative and Reconstructive Surgery, 2017, 31(1): 105-109. doi: 10.7507/1002-1892.201609008 Copy

1.	Anastasia A, Barker PA, Chao MV, et al. Detection of p75NTR trimers: implications for receptor stoichiometry and activation. J Neurosci, 2015, 35(34): 11911-11920.
2.	Tanaka K, Kelly CE, Goh KY, et al. Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS. J Neurosci, 2016, 36(20): 5587-5595.
3.	Lin Z, Tann JY, Goh ET, et al. Structural basis of death domain signaling in the p75 neurotrophin receptor. Elife, 2015, 4: e11692.
4.	Shu YH, Lu XM, Wei JX, et al. Update on the role of p75NTR in neurological disorders: A novel therapeutic target. Biomed Pharmacother, 2015, 76: 17-23.
5.	Rahbek UL, Dissing S, Thomassen C, et al. Nerve growth factor activates aorta endothelial cells causing PI3K/Akt- and ERK-dependent migration. Pflugers Arch, 2005, 450(5): 355-361.
6.	Majdan M, Walsh GS, Aloyz R, et al. TrkA mediates developmental sympathetic neuron survivalin vivo by silencing an ongoing p75NTR-mediated death signal. J Cell Biol, 2001, 155(7): 1275-1285.
7.	De la Cruz-Morcillo MA, Berger J, Sánchez-Prieto R, et al. p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma. Oncotarget, 2016, 7(23): 34480-34497.
8.	Schweigreiter R. The dual nature of neurotrophins. Bioessays, 2006, 28(6): 583-594.
9.	De la Cruz-Morcillo MA, Berger J, Sánchez-Prieto R, et al. p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma. Oncotarget, 2016, 7(23): 34480-34497.
10.	Nykjaer A, Willnow TE. Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci, 2012, 35(4): 261-270.
11.	于立明, 张伟, 陈坤, 等. 神经生长因子及其受体在下颌骨骨折愈合中的表达及意义. 实用口腔医学杂志, 2011, 27(4): 460-464.
12.	Twiss JL, Chang JH, Schanen NC. Pathophysiological mechanisms for actions of the neurotrophins. Brain Pathol, 2006, 16(4): 320-332.
13.	曾志青, 刘洪, 蒋迪. 神经营养因子受体同源物 2 通过上调 proNGF、sortilin、p75NTR 表达诱导脑出血后血肿周围脑组织细胞凋亡. 细胞与分子免疫学杂志, 2015, 31(4): 532-536, 539.
14.	Meeker R, Williams K. Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol, 2014, 9(5): 615-628.
15.	Tomita K, Kubo T, Matsuda K, et al. The neurotrophin receptor p75NTR in Schwann cells is implicated in remyelination and motor recovery after peripheral nerve injury. Glia, 2007, 55(11): 1199-1208.
16.	Delbary-Gossart S, Lee S, Baroni M, et al. A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury. Brain, 2016, 139(Pt 6): 1762-1782.
17.	Courter LA, Shaffo FC, Ghogha A, et al. BMP7-induced dendritic growth in sympathetic neurons requires p75(NTR) signaling. Dev Neurobiol, 2016, 76(9): 1003-1013.
18.	Tazi A, Le BS, Lamghitnia HO, et al. Neurotrophin-3 increases intracellular calcium in a rat insulin-secreting cell line through its action on a functional TrkC receptor. J Biol Chem, 1996, 271(17): 10154-10160.
19.	Matusica D, Alfonsi F, Turner BJ, et al. Inhibition of motor neuron death in vitro andin vivo by a p75 neurotrophin receptor intracellular domain fragment. J Cell Sci, 2016, 129(3): 517-530.
20.	Sebastiani A, Gölz C, Werner C, et al. Proneurotrophin Binding to P75 Neurotrophin Receptor (P75ntr) Is Essential for Brain Lesion Formation and Functional Impairment after Experimental Traumatic Brain Injury. J Neurotrauma, 2015, 32(20): 1599-1607.
21.	Delbary-Gossart S, Lee S, Baroni M, et al. A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury. Brain, 2016, 139(Pt 6): 1762-1782.
22.	Caporali A, Pani E, Horrevoets AJ, et al. Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles. Circ Res, 2008, 103(2): e15-26.
23.	Shanab AY, Mysona BA, Matragoon S, et al. Silencing p75(NTR) prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina. Mol Ther Methods Clin Dev, 2015, 2: 15013.
24.	Caporali A, Meloni M, Miller AM, et al. Soluble ST2 is regulated by p75 neurotrophin receptor and predicts mortality in diabetic patients with critical limb ischemia. Arterioscler Thromb Vasc Biol, 2012, 32(12): e149-160.
25.	Graiani G, Emanueli C, Desortes E, et al. Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice. Diabetologia, 2004, 47(6): 1047-1054.
26.	Tahiri H, Yang C, Duhamel F, et al. p75 neurotrophin receptor participates in the choroidal antiangiogenic and apoptotic effects of T-lymphocyte-derived microparticles. Invest Ophthalmol Vis Sci, 2013, 54(9): 6084-6092.
27.	Meuchel LW, Thompson MA, Cassivi SD, et al. Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells. Cardiovasc Res, 2011, 91(4): 668-676.
28.	Sachs BD, Baillie GS, McCall JR, et al. p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. J Cell Biol, 2007, 177(6): 1119-1132.
29.	Wang S, Bray P, McCaffrey T, et al. p75(NTR) mediates neurotrophin-induced apoptosis of vascular smooth muscle cells. Am J Pathol, 2000, 157(4): 1247-1258.
30.	Herrmann JL, Menter DG, Hamada J, et al. Mediation of NGF-stimulated extracellular matrix invasion by the human melanoma low-affinity p75 neurotrophin receptor: melanoma p75 functions independently of trkA. Mol Biol Cell, 1993, 4(11): 1205-1216.
31.	Renz H, Kerzel S, Nockher WA. The role of neurotrophins in bronchial asthma: contribution of the pan-neurotrophin receptor p75. Prog Brain Res, 2004, 146: 325-333.
32.	Amoras Eda S, Gomes ST, Freitas FB, et al. NGF and P75NTR gene expression is associated with the hepatic fibrosis stage due to viral and non-viral causes. PLoS One, 2015, 10(3): e0121754. doi: 10.1371/journal.pone.0121754.eCollection 2015.
33.	Schwabe P, Simon P, Kronbach Z, et al. A pilot study investigating the histology and growth factor content of human non-union tissue. Int Orthop, 2014, 38(12): 2623-2629.
34.	Koga T, Lee SY, Niikura T, et al. Effect of low-intensity pulsed ultrasound on bone morphogenetic protein 7-induced osteogenic differentiation of human nonunion tissue-derived cellsin vitro. J Ultrasound Med, 2013, 32(6): 915-922.
35.	Cole HA, Ohba T, Nyman JS, et al. Fibrin accumulation secondary to loss of plasmin-mediated fibrinolysis drives inflammatory osteoporosis in mice. Arthritis Rheumatol, 2014, 66(8): 2222-2233.
36.	Yuasa M, Mignemi NA, Nyman JS, et al. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification. J Clin Invest, 2015, 125(8): 3117-3131.
37.	Ko KI, Coimbra LS, Tian C, et al. Diabetes reduces mesenchymal stem cells in fracture healing through a TNFalpha-mediated mechanism. Diabetologia, 2015, 58(3): 633-642.
38.	Karnes JM, Daffner SD, Watkins CM. Multiple roles of tumor necrosis factor-alpha in fracture healing. Bone, 2015, 78: 87-93.
39.	Maes C, Kobayashi T, Selig MK, et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell, 2010, 19(2): 329-344.
40.	Bothwell M. Recent advances in understanding neurotrophin signaling. F1000Res, 2016, 5. pii: F1000 Faculty Rev-1885. doi: 10.12688/f1000research.8434.1.eCollection 2016.

1. Anastasia A, Barker PA, Chao MV, et al. Detection of p75NTR trimers: implications for receptor stoichiometry and activation. J Neurosci, 2015, 35(34): 11911-11920.
2. Tanaka K, Kelly CE, Goh KY, et al. Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS. J Neurosci, 2016, 36(20): 5587-5595.
3. Lin Z, Tann JY, Goh ET, et al. Structural basis of death domain signaling in the p75 neurotrophin receptor. Elife, 2015, 4: e11692.
4. Shu YH, Lu XM, Wei JX, et al. Update on the role of p75NTR in neurological disorders: A novel therapeutic target. Biomed Pharmacother, 2015, 76: 17-23.
5. Rahbek UL, Dissing S, Thomassen C, et al. Nerve growth factor activates aorta endothelial cells causing PI3K/Akt- and ERK-dependent migration. Pflugers Arch, 2005, 450(5): 355-361.
6. Majdan M, Walsh GS, Aloyz R, et al. TrkA mediates developmental sympathetic neuron survivalin vivo by silencing an ongoing p75NTR-mediated death signal. J Cell Biol, 2001, 155(7): 1275-1285.
7. De la Cruz-Morcillo MA, Berger J, Sánchez-Prieto R, et al. p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma. Oncotarget, 2016, 7(23): 34480-34497.
8. Schweigreiter R. The dual nature of neurotrophins. Bioessays, 2006, 28(6): 583-594.
9. De la Cruz-Morcillo MA, Berger J, Sánchez-Prieto R, et al. p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma. Oncotarget, 2016, 7(23): 34480-34497.
10. Nykjaer A, Willnow TE. Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci, 2012, 35(4): 261-270.
11. 于立明, 张伟, 陈坤, 等. 神经生长因子及其受体在下颌骨骨折愈合中的表达及意义. 实用口腔医学杂志, 2011, 27(4): 460-464.
12. Twiss JL, Chang JH, Schanen NC. Pathophysiological mechanisms for actions of the neurotrophins. Brain Pathol, 2006, 16(4): 320-332.
13. 曾志青, 刘洪, 蒋迪. 神经营养因子受体同源物 2 通过上调 proNGF、sortilin、p75NTR 表达诱导脑出血后血肿周围脑组织细胞凋亡. 细胞与分子免疫学杂志, 2015, 31(4): 532-536, 539.
14. Meeker R, Williams K. Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol, 2014, 9(5): 615-628.
15. Tomita K, Kubo T, Matsuda K, et al. The neurotrophin receptor p75NTR in Schwann cells is implicated in remyelination and motor recovery after peripheral nerve injury. Glia, 2007, 55(11): 1199-1208.
16. Delbary-Gossart S, Lee S, Baroni M, et al. A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury. Brain, 2016, 139(Pt 6): 1762-1782.
17. Courter LA, Shaffo FC, Ghogha A, et al. BMP7-induced dendritic growth in sympathetic neurons requires p75(NTR) signaling. Dev Neurobiol, 2016, 76(9): 1003-1013.
18. Tazi A, Le BS, Lamghitnia HO, et al. Neurotrophin-3 increases intracellular calcium in a rat insulin-secreting cell line through its action on a functional TrkC receptor. J Biol Chem, 1996, 271(17): 10154-10160.
19. Matusica D, Alfonsi F, Turner BJ, et al. Inhibition of motor neuron death in vitro andin vivo by a p75 neurotrophin receptor intracellular domain fragment. J Cell Sci, 2016, 129(3): 517-530.
20. Sebastiani A, Gölz C, Werner C, et al. Proneurotrophin Binding to P75 Neurotrophin Receptor (P75ntr) Is Essential for Brain Lesion Formation and Functional Impairment after Experimental Traumatic Brain Injury. J Neurotrauma, 2015, 32(20): 1599-1607.
21. Delbary-Gossart S, Lee S, Baroni M, et al. A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury. Brain, 2016, 139(Pt 6): 1762-1782.
22. Caporali A, Pani E, Horrevoets AJ, et al. Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles. Circ Res, 2008, 103(2): e15-26.
23. Shanab AY, Mysona BA, Matragoon S, et al. Silencing p75(NTR) prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina. Mol Ther Methods Clin Dev, 2015, 2: 15013.
24. Caporali A, Meloni M, Miller AM, et al. Soluble ST2 is regulated by p75 neurotrophin receptor and predicts mortality in diabetic patients with critical limb ischemia. Arterioscler Thromb Vasc Biol, 2012, 32(12): e149-160.
25. Graiani G, Emanueli C, Desortes E, et al. Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice. Diabetologia, 2004, 47(6): 1047-1054.
26. Tahiri H, Yang C, Duhamel F, et al. p75 neurotrophin receptor participates in the choroidal antiangiogenic and apoptotic effects of T-lymphocyte-derived microparticles. Invest Ophthalmol Vis Sci, 2013, 54(9): 6084-6092.
27. Meuchel LW, Thompson MA, Cassivi SD, et al. Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells. Cardiovasc Res, 2011, 91(4): 668-676.
28. Sachs BD, Baillie GS, McCall JR, et al. p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. J Cell Biol, 2007, 177(6): 1119-1132.
29. Wang S, Bray P, McCaffrey T, et al. p75(NTR) mediates neurotrophin-induced apoptosis of vascular smooth muscle cells. Am J Pathol, 2000, 157(4): 1247-1258.
30. Herrmann JL, Menter DG, Hamada J, et al. Mediation of NGF-stimulated extracellular matrix invasion by the human melanoma low-affinity p75 neurotrophin receptor: melanoma p75 functions independently of trkA. Mol Biol Cell, 1993, 4(11): 1205-1216.
31. Renz H, Kerzel S, Nockher WA. The role of neurotrophins in bronchial asthma: contribution of the pan-neurotrophin receptor p75. Prog Brain Res, 2004, 146: 325-333.
32. Amoras Eda S, Gomes ST, Freitas FB, et al. NGF and P75NTR gene expression is associated with the hepatic fibrosis stage due to viral and non-viral causes. PLoS One, 2015, 10(3): e0121754. doi: 10.1371/journal.pone.0121754.eCollection 2015.
33. Schwabe P, Simon P, Kronbach Z, et al. A pilot study investigating the histology and growth factor content of human non-union tissue. Int Orthop, 2014, 38(12): 2623-2629.
34. Koga T, Lee SY, Niikura T, et al. Effect of low-intensity pulsed ultrasound on bone morphogenetic protein 7-induced osteogenic differentiation of human nonunion tissue-derived cellsin vitro. J Ultrasound Med, 2013, 32(6): 915-922.
35. Cole HA, Ohba T, Nyman JS, et al. Fibrin accumulation secondary to loss of plasmin-mediated fibrinolysis drives inflammatory osteoporosis in mice. Arthritis Rheumatol, 2014, 66(8): 2222-2233.
36. Yuasa M, Mignemi NA, Nyman JS, et al. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification. J Clin Invest, 2015, 125(8): 3117-3131.
37. Ko KI, Coimbra LS, Tian C, et al. Diabetes reduces mesenchymal stem cells in fracture healing through a TNFalpha-mediated mechanism. Diabetologia, 2015, 58(3): 633-642.
38. Karnes JM, Daffner SD, Watkins CM. Multiple roles of tumor necrosis factor-alpha in fracture healing. Bone, 2015, 78: 87-93.
39. Maes C, Kobayashi T, Selig MK, et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell, 2010, 19(2): 329-344.
40. Bothwell M. Recent advances in understanding neurotrophin signaling. F1000Res, 2016, 5. pii: F1000 Faculty Rev-1885. doi: 10.12688/f1000research.8434.1.eCollection 2016.

Chinese Journal of Reparative and Reconstructive Surgery

Research progress of P75 neurotrophin receptor and new idea of nonunion treatment

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