Inflammation contributes to the spontaneous regression of spinal disc herniation
A.M. Tkachev1,2, A.V. Epifanov3, E.S. Akarachkova4, A.V. Smirnova1, A.V. Iljushin1, D.S. Archakov2
1Sergey Berezin Medical Institute, Volgograd
2Tkachev Medical Clinic, Volgograd
3Doctor Epifanov Clinic, Samara
4International Society for Stress “Stress under control”, Moscow
High prevalence of low back pain (predominantly, lumbar backache) resulting from herniated discs requires careful study of the pathogenesis of this disorder to improve preventive and therapeutic interventions. Lumbar disc herniation is associated with inflammation. Currently, inflammation is considered to be associated with unfavorable symptoms resulting from nerve ending stimulation which leads to pain. However, inflammation is also regarded as one of the key factors of the regression of lumbar disc herniation. The paper discusses molecular and cellular mechanisms involved in the regression of lumbar disc herniation including matrix remodeling and neovascularization. Inflammatory response in lumbar disc herniation and, in particular, the role of monocytes and macrophages are highlighted. Investigati on of cytokine and immune cell contribution to intervertebral disc degeneration, inflammation, and nociception may provide potential therapeutic targets in patients with symptomatic disc herniation. As a result, their quality of life will be improved.
Keywords: lumbar disc herniation, intervertebral disc, inflammation, macrophages, monocytes.
For citation: Tkachev A.M., Epifanov A.V., Akarachkova E.S. et al. Inflammation contributes to the spontaneous regression of spinal disc herniation. RMJ. Medical Review. 2019;7:30–33.
References
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2. Brinjikji W., Luetmer P.H., Comstock B. et al. Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. AJNR Am J Neuroradiol. 2015;36(4):811–816.
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6. Purmessur D., Walter B.A., Roughley P.J. et al. A role for TNFα in intervertebral disc degeneration: a non-recoverable catabolic shift. Biochem Biophys Res Commun. 2013;433:151–156.
7. Shen C., Yan J., Jiang L.S., Dai L.Y. Autophagy in rat annulus fibrosus cells: evidence and possible implications. Arthritis Res Ther. 2011;13:132.
8. Hodges P.W., James G., Blomster L. et al. Can proinflammatory cytokine gene expression explain multifidus muscle fiber changes after an intervertebral disc lesion? Spine (Phila Pa 1976). 2014;39(13):1010–1017.
9. Cuéllar J.M., Borges P.M., Cuéllar V.G. et al. Cytokine expression in the epidural space: a model of noncompressive disc herniation-induced inflammation. Spine (Phila Pa 1976). 2013;38:17–23.
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11. Wang J., Markova D., Anderson D.G. 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;286:39738–39749.
12. Bachmeier B.E., Nerlich A., Mittermaier N. et al. Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration. Eur Spine J. 2009;18:1573–1586.
13. Кадырова Л.Р., Акарачкова Е.С., Керимова К.С. и др. Мультидисциплинарный подход к пациенту с хронической болью. РМЖ. 2018;7:28–32. [Kadyrova L.R., Akarachkova E.S., Kerimova K.S. et al. Multidisciplinary approach to patient with chronic pain. RMJ. 2018;7:28–32 (in Russ.)].
14. Macki M., Hernandez-Hermann M., Bydon M. et al. Spontaneous regression of sequestrated lumbar disc herniations: literature review. Clin Neurol Neurosurg. 2014;120:136–141.
15. Голубенко Е.О., Силина Е.В., Орлова А.С. Персонифицированный подход в лечении болевых синдромов. Современная наука: актуальные проблемы теории и практики. Серия: Естественные и технические науки. 2017;7–8:107–112. [Golubenko E.O., Silina E.V., Orlova A.S. Personalized medicine in pain management. Sovremennaya nauka: aktual’nye problemy teorii i praktiki. Seriya: Estestvennye i tekhnicheskie nauki. 2017;7–8:107–112 (in Russ.)].
16. Кулешов А.А., Крупаткин А.И., Муравьева Н.В. Спонтанная резорбция грыж межпозвонковых дисков. Вестник травматологии и ортопедии им. Н.Н. Приорова. 2016;3:81–89. [Kuleshov A.A., Krupatkin A.I., Murav’yova N.V. Spontaneous Resorption of Intervertebral Disc Herniations. Vestnik travmatologii i ortopedii im. N.N. Priorova. 2016;3:81–89 (in Russ.)].
17. Ткачев А.М., Акарачкова Е.С., Смирнова А.В. и др. Спонтанный регресс грыж межпозвонковых дисков поясничного отдела позвоночника на фоне терапии габапентином. Фарматека. 2017;19:20–24. [Tkachev A.M., Akarachkova E.S., Smirnova A.V. et al. Spontaneous regression of lumbar disc herniations against the background of therapy with gabapentin. Farmateka. 2017;19:20–24 (in Russ.)].
18. Zhong M., Liu J.T., Jiang H. et al. Incidence of Spontaneous Resorption of Lumbar Disc Herniation: A Meta-Analysis. Pain Physician. 2017;20(1):45–52.
19. Kobayashi S., Meir A., Kokubo Y. et al. Ultrastructural analysis on lumbar disc herniation using surgical specimens: role of neovascularization and macrophages in hernias. Spine. 2009;34(7): 655–662.
20. Zhang Y., Chee A., Shi P. et al. Intervertebral Disc Cells Produce Interleukins Found in Patients with Back Pain. Am J Phys Med Rehabil. 2016;95(6):407–415.
21. Hiyama A., Mochida J., Sakai D. Stem cell applications in intervertebral disc repair. Cell Mol Biol. 2008;54(1):24–32.
22. Yamamoto J., Maeno K., Takada T. et al. Fas ligand plays an important role for the production of pro-inflammatory cytokines in intervertebral disc nucleus pulposus cells. J Orthop Res. 2013;31(4):608–615.
23. Doita M., Kanatani T., Ozaki T. et al. Influence of macrophage infiltration of herniated disc tissue on the production of matrix metalloproteinases leading to disc resorption. Spine. 2001;26(14):1522–1527.
24. Austin P.J., Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol. 2010;229:26–50.
25. Hirsch C., Schajowicz F. Studies on structural changes in the lumbar annulus fibrosus. Acta Orthop Scand. 1953;22:184–231.
26. Di Martino A., Merlini L., Faldini C. Autoimmunity in intervertebral disc herniation: from bench to bedside. Expert Opin Ther Targets. 2013;17(12):1461–1470.
27. Ohtori S., Inoue G., Eguchi Y. et al. Tumor necrosis factor-α-immunoreactive cells in nucleus pulposus in adolescent patients with lumbar disc herniation. Spine (Phila Pa 1976). 2013;38(6):459–462.
28. Koike Y., Uzuki M., Kokubun S., Sawai T. Angiogenesis and inflammatory cell infiltration in lumbar disc herniation. Spine. 2003;28(17):1928–1933.
29. Shamji M.F., Setton L.A., Jarvis W. et al. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum. 2010;62(7):1974–1982.
30. Henson P.M. Mechanisms of exocytosis in phagocytic inflammatory cells. Parke-Davis Award Lecture. Am J Pathol. 1980;101(3):494–511.
31. Molinos M., Almeida C.R., Caldeira J. et al. Inflammation in intervertebral disc degeneration and regeneration. J R Soc Interface. 2015;12(108):20150429.
32. Burke J.G., Watson R.W., McCormack D. et al. Spontaneous production of monocyte chemoattractant protein-1 and interleukin-8 by the human lumbar intervertebral disc. Spine. 2002;27(13):1402–1407.
33. Yoshida M., Nakamura T., Kikuchi T. et al. Expression of monocyte chemoattractant protein-1 in primary cultures of rabbit intervertebral disc cells. J Orthop Res. 2002;20(6):1298–1304.
34. Geiss A., Sobottke R., Delank K.S., Eysel P. Plasmacytoid dendritic cells and memory T cells infiltrate true sequestrations stronger than subligamentous sequestrations: evidence from flow cytometric analysis of disc infiltrates. Eur Spine J. 2016;25(5):1417–1427.
35. Kang J.D., Stefanovic-Racic M., McIntyre L.A. et al. Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine. 1997;22(10):1065–1073.
36. Deng X., Zhao F., Kang B., Zhang X. Elevated interleukin-6 expression levels are associated with intervertebral disc degeneration. Exp Ther Med. 2016;11(4):1425–1432.
37. Takada T., Nishida K., Maeno K. et al. Intervertebral disc and macrophage interaction induces mechanical hyperalgesia and cytokine production in a herniated disc model in rats. Arthritis Rheum. 2012;64(8):2601–2610.
38. Cunha C., Lamas S., Goncalves R.M., Barbosa M.A. Joint analysis of IVD herniation and degeneration by rat caudal needle puncture model. J Orthop Res. 2017;35(2):258–268.
39. Geiss A., Larsson K., Junevik K. et al. Autologous nucleus pulposus primes T cells to develop into interleukin-4-producing effector cells: an experimental study on the autoimmune properties of nucleus pulposus. J Orthop Res. 2009;27(1):97–103.
40. Virri J., Gronblad M., Seitsalo S. et al. Comparison of the prevalence of inflammatory cells in subtypes of disc herniations and associations with straight leg raising. Spine. 2001;26(21):2311–2315.
41. Navone S.E., Marfia G., Giannoni A. et al. Inflammatory mediators and signalling pathways controlling intervertebral disc degeneration. Histol Histopathol. 2017;32(6):523–542.
42. Pohl P.H., Lozito T.P., Cuperman T. et al. Catabolic effects of endothelial cell-derived microparticles on disc cells: Implications in intervertebral disc neovascularization and degeneration. J Orthop Res. 2016;34(8):1466–1474.
43. Capossela S., Bertolo A., Gunasekera K. et al. VEGF vascularization pathway in human intervertebral disc does not change during the disc degeneration process. BMC Res Notes. 2018;11(1):333.
44. Jia C.Q., Zhao J.G., Zhang S.F., Qi F. Stromal cell-derived factor-1 and vascular endothelial growth factor may play an important role in the process of neovascularization of herniated intervertebral discs. J Int Med Res. 2009;37(1):136–144.
45. Wang F., Cai F., Shi R. et al. Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthritis Cartilage. 2016;24(3):398–408.
46. Melrose J., Roberts S., Smith S. et al. Increased nerve and blood vessel ingrowth associated with proteoglycan depletion in an ovine anular lesion model of experimental disc degeneration. Spine (Phila Pa 1976). 2002;27:1278–1285.
47. Aoki Y., Nakajima A., Ohtori S. et al. Increase of nerve growth factor levels in the human herniated intervertebral disc: can annular rupture trigger discogenic back pain? Arthritis Res Ther. 2014;16(4):159.
48. Tian Y., Yuan W., Fujita N. et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol. 2013;182(6):2310–2321.
49. Purmessur D., Freemont A.J., Hoyland J.A. Expression and regulation of neurotrophins in the nondegenerate and degenerate human intervertebral disc. Arthritis Res Ther. 2008;10:R99.
50. Gruber H.E., Hoelscher G.L., Bethea S., Hanley E.N. Jr. Interleukin 1-beta upregulates brain-derived neurotrophic factor, neurotrophin 3 and neuropilin 2 gene expression and NGF production in annulus cells. Biotech Histochem. 2012;87:506–511.
51. Uchiyama Y., Cheng C.C., Danielson K.G. et al. Expression of acid-sensing ion channel 3 (ASIC3) in nucleus pulposus cells of the intervertebral disc is regulated by p75NTR and ERK signaling. J Bone Miner Res. 2007;22:1996–2006.
52. Andrade P., Hoogland G., Garcia M.A. et al. Elevated IL-1β and IL-6 levels in lumbar herniated discs in patients with sciatic pain. Eur Spine J. 2013;22:714–720.
53. Ebbinghaus M. et al. The role of interleukin-1β in arthritic pain: main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. Arthritis Rheum. 2012;64:3897–3907.
54. Xiao L., Hong K., Roberson C. et al. Hydroxylated Fullerene: A Stellar Nanomedicine to Treat Lumbar Radiculopathy via Antagonizing TNF-α-Induced Ion Channel Activation, Calcium Signaling, and Neuropeptide Production. ACS Biomater Sci Eng. 2018;4(1):266–277.
55. García-Cosamalón J., del Valle M.E., Calavia M.G. et al. Intervertebral disc, sensory nerves and neurotrophins: who is who in discogenic pain? J Anat. 2010;217:1–15.
2. Brinjikji W., Luetmer P.H., Comstock B. et al. Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. AJNR Am J Neuroradiol. 2015;36(4):811–816.
3. Rajasekaran S., Bajaj N., Tubaki V. et al. ISSLS Prize winner: The anatomy of failure in lumbar disc herniation: an in vivo, multimodal, prospective study of 181 subjects. Spine. 2013;38(17):1491–1500.
4. Yamamoto J., Maeno K., Takada T. et al. Fas ligand plays an important role for the production of pro-inflammatory cytokines in intervertebral disc nucleus pulposus cells. J Orthop Res. 2013;31:608–615.
5. Kepler C.K., Markova D.Z., Koerner J.D. et al. Substance P Receptor Antagonist Suppresses Inflammatory Cytokine Expression in Human Disc Cells. Spine (Phila Pa 1976). 2015;40(16):1261–1269.
6. Purmessur D., Walter B.A., Roughley P.J. et al. A role for TNFα in intervertebral disc degeneration: a non-recoverable catabolic shift. Biochem Biophys Res Commun. 2013;433:151–156.
7. Shen C., Yan J., Jiang L.S., Dai L.Y. Autophagy in rat annulus fibrosus cells: evidence and possible implications. Arthritis Res Ther. 2011;13:132.
8. Hodges P.W., James G., Blomster L. et al. Can proinflammatory cytokine gene expression explain multifidus muscle fiber changes after an intervertebral disc lesion? Spine (Phila Pa 1976). 2014;39(13):1010–1017.
9. Cuéllar J.M., Borges P.M., Cuéllar V.G. et al. Cytokine expression in the epidural space: a model of noncompressive disc herniation-induced inflammation. Spine (Phila Pa 1976). 2013;38:17–23.
10. Hayashi S., Taira A., Inoue G. et al. TNF-alpha in nucleus pulposus induces sensory nerve growth: a study of the mechanism of discogenic low back pain using TNF-alpha-deficient mice. Spine (Phila Pa 1976). 2008;33:1542–1546.
11. Wang J., Markova D., Anderson D.G. 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;286:39738–39749.
12. Bachmeier B.E., Nerlich A., Mittermaier N. et al. Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration. Eur Spine J. 2009;18:1573–1586.
13. Кадырова Л.Р., Акарачкова Е.С., Керимова К.С. и др. Мультидисциплинарный подход к пациенту с хронической болью. РМЖ. 2018;7:28–32. [Kadyrova L.R., Akarachkova E.S., Kerimova K.S. et al. Multidisciplinary approach to patient with chronic pain. RMJ. 2018;7:28–32 (in Russ.)].
14. Macki M., Hernandez-Hermann M., Bydon M. et al. Spontaneous regression of sequestrated lumbar disc herniations: literature review. Clin Neurol Neurosurg. 2014;120:136–141.
15. Голубенко Е.О., Силина Е.В., Орлова А.С. Персонифицированный подход в лечении болевых синдромов. Современная наука: актуальные проблемы теории и практики. Серия: Естественные и технические науки. 2017;7–8:107–112. [Golubenko E.O., Silina E.V., Orlova A.S. Personalized medicine in pain management. Sovremennaya nauka: aktual’nye problemy teorii i praktiki. Seriya: Estestvennye i tekhnicheskie nauki. 2017;7–8:107–112 (in Russ.)].
16. Кулешов А.А., Крупаткин А.И., Муравьева Н.В. Спонтанная резорбция грыж межпозвонковых дисков. Вестник травматологии и ортопедии им. Н.Н. Приорова. 2016;3:81–89. [Kuleshov A.A., Krupatkin A.I., Murav’yova N.V. Spontaneous Resorption of Intervertebral Disc Herniations. Vestnik travmatologii i ortopedii im. N.N. Priorova. 2016;3:81–89 (in Russ.)].
17. Ткачев А.М., Акарачкова Е.С., Смирнова А.В. и др. Спонтанный регресс грыж межпозвонковых дисков поясничного отдела позвоночника на фоне терапии габапентином. Фарматека. 2017;19:20–24. [Tkachev A.M., Akarachkova E.S., Smirnova A.V. et al. Spontaneous regression of lumbar disc herniations against the background of therapy with gabapentin. Farmateka. 2017;19:20–24 (in Russ.)].
18. Zhong M., Liu J.T., Jiang H. et al. Incidence of Spontaneous Resorption of Lumbar Disc Herniation: A Meta-Analysis. Pain Physician. 2017;20(1):45–52.
19. Kobayashi S., Meir A., Kokubo Y. et al. Ultrastructural analysis on lumbar disc herniation using surgical specimens: role of neovascularization and macrophages in hernias. Spine. 2009;34(7): 655–662.
20. Zhang Y., Chee A., Shi P. et al. Intervertebral Disc Cells Produce Interleukins Found in Patients with Back Pain. Am J Phys Med Rehabil. 2016;95(6):407–415.
21. Hiyama A., Mochida J., Sakai D. Stem cell applications in intervertebral disc repair. Cell Mol Biol. 2008;54(1):24–32.
22. Yamamoto J., Maeno K., Takada T. et al. Fas ligand plays an important role for the production of pro-inflammatory cytokines in intervertebral disc nucleus pulposus cells. J Orthop Res. 2013;31(4):608–615.
23. Doita M., Kanatani T., Ozaki T. et al. Influence of macrophage infiltration of herniated disc tissue on the production of matrix metalloproteinases leading to disc resorption. Spine. 2001;26(14):1522–1527.
24. Austin P.J., Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol. 2010;229:26–50.
25. Hirsch C., Schajowicz F. Studies on structural changes in the lumbar annulus fibrosus. Acta Orthop Scand. 1953;22:184–231.
26. Di Martino A., Merlini L., Faldini C. Autoimmunity in intervertebral disc herniation: from bench to bedside. Expert Opin Ther Targets. 2013;17(12):1461–1470.
27. Ohtori S., Inoue G., Eguchi Y. et al. Tumor necrosis factor-α-immunoreactive cells in nucleus pulposus in adolescent patients with lumbar disc herniation. Spine (Phila Pa 1976). 2013;38(6):459–462.
28. Koike Y., Uzuki M., Kokubun S., Sawai T. Angiogenesis and inflammatory cell infiltration in lumbar disc herniation. Spine. 2003;28(17):1928–1933.
29. Shamji M.F., Setton L.A., Jarvis W. et al. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum. 2010;62(7):1974–1982.
30. Henson P.M. Mechanisms of exocytosis in phagocytic inflammatory cells. Parke-Davis Award Lecture. Am J Pathol. 1980;101(3):494–511.
31. Molinos M., Almeida C.R., Caldeira J. et al. Inflammation in intervertebral disc degeneration and regeneration. J R Soc Interface. 2015;12(108):20150429.
32. Burke J.G., Watson R.W., McCormack D. et al. Spontaneous production of monocyte chemoattractant protein-1 and interleukin-8 by the human lumbar intervertebral disc. Spine. 2002;27(13):1402–1407.
33. Yoshida M., Nakamura T., Kikuchi T. et al. Expression of monocyte chemoattractant protein-1 in primary cultures of rabbit intervertebral disc cells. J Orthop Res. 2002;20(6):1298–1304.
34. Geiss A., Sobottke R., Delank K.S., Eysel P. Plasmacytoid dendritic cells and memory T cells infiltrate true sequestrations stronger than subligamentous sequestrations: evidence from flow cytometric analysis of disc infiltrates. Eur Spine J. 2016;25(5):1417–1427.
35. Kang J.D., Stefanovic-Racic M., McIntyre L.A. et al. Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine. 1997;22(10):1065–1073.
36. Deng X., Zhao F., Kang B., Zhang X. Elevated interleukin-6 expression levels are associated with intervertebral disc degeneration. Exp Ther Med. 2016;11(4):1425–1432.
37. Takada T., Nishida K., Maeno K. et al. Intervertebral disc and macrophage interaction induces mechanical hyperalgesia and cytokine production in a herniated disc model in rats. Arthritis Rheum. 2012;64(8):2601–2610.
38. Cunha C., Lamas S., Goncalves R.M., Barbosa M.A. Joint analysis of IVD herniation and degeneration by rat caudal needle puncture model. J Orthop Res. 2017;35(2):258–268.
39. Geiss A., Larsson K., Junevik K. et al. Autologous nucleus pulposus primes T cells to develop into interleukin-4-producing effector cells: an experimental study on the autoimmune properties of nucleus pulposus. J Orthop Res. 2009;27(1):97–103.
40. Virri J., Gronblad M., Seitsalo S. et al. Comparison of the prevalence of inflammatory cells in subtypes of disc herniations and associations with straight leg raising. Spine. 2001;26(21):2311–2315.
41. Navone S.E., Marfia G., Giannoni A. et al. Inflammatory mediators and signalling pathways controlling intervertebral disc degeneration. Histol Histopathol. 2017;32(6):523–542.
42. Pohl P.H., Lozito T.P., Cuperman T. et al. Catabolic effects of endothelial cell-derived microparticles on disc cells: Implications in intervertebral disc neovascularization and degeneration. J Orthop Res. 2016;34(8):1466–1474.
43. Capossela S., Bertolo A., Gunasekera K. et al. VEGF vascularization pathway in human intervertebral disc does not change during the disc degeneration process. BMC Res Notes. 2018;11(1):333.
44. Jia C.Q., Zhao J.G., Zhang S.F., Qi F. Stromal cell-derived factor-1 and vascular endothelial growth factor may play an important role in the process of neovascularization of herniated intervertebral discs. J Int Med Res. 2009;37(1):136–144.
45. Wang F., Cai F., Shi R. et al. Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthritis Cartilage. 2016;24(3):398–408.
46. Melrose J., Roberts S., Smith S. et al. Increased nerve and blood vessel ingrowth associated with proteoglycan depletion in an ovine anular lesion model of experimental disc degeneration. Spine (Phila Pa 1976). 2002;27:1278–1285.
47. Aoki Y., Nakajima A., Ohtori S. et al. Increase of nerve growth factor levels in the human herniated intervertebral disc: can annular rupture trigger discogenic back pain? Arthritis Res Ther. 2014;16(4):159.
48. Tian Y., Yuan W., Fujita N. et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol. 2013;182(6):2310–2321.
49. Purmessur D., Freemont A.J., Hoyland J.A. Expression and regulation of neurotrophins in the nondegenerate and degenerate human intervertebral disc. Arthritis Res Ther. 2008;10:R99.
50. Gruber H.E., Hoelscher G.L., Bethea S., Hanley E.N. Jr. Interleukin 1-beta upregulates brain-derived neurotrophic factor, neurotrophin 3 and neuropilin 2 gene expression and NGF production in annulus cells. Biotech Histochem. 2012;87:506–511.
51. Uchiyama Y., Cheng C.C., Danielson K.G. et al. Expression of acid-sensing ion channel 3 (ASIC3) in nucleus pulposus cells of the intervertebral disc is regulated by p75NTR and ERK signaling. J Bone Miner Res. 2007;22:1996–2006.
52. Andrade P., Hoogland G., Garcia M.A. et al. Elevated IL-1β and IL-6 levels in lumbar herniated discs in patients with sciatic pain. Eur Spine J. 2013;22:714–720.
53. Ebbinghaus M. et al. The role of interleukin-1β in arthritic pain: main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. Arthritis Rheum. 2012;64:3897–3907.
54. Xiao L., Hong K., Roberson C. et al. Hydroxylated Fullerene: A Stellar Nanomedicine to Treat Lumbar Radiculopathy via Antagonizing TNF-α-Induced Ion Channel Activation, Calcium Signaling, and Neuropeptide Production. ACS Biomater Sci Eng. 2018;4(1):266–277.
55. García-Cosamalón J., del Valle M.E., Calavia M.G. et al. Intervertebral disc, sensory nerves and neurotrophins: who is who in discogenic pain? J Anat. 2010;217:1–15.
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