The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling

Science Translational Medicine

Volumn 8, Issue 325, 2016, Pages

  Maiarù, Maria ^a   Tochiki, Keri K ^a   Cox, Marc B ^b   Annan, Leonette V ^a,f   Bell, Christopher G ^c,d   Feng, Xixi ^e   Hausch, Felix ^e   Géranton, Sandrine M ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF TEXAS AT EL PASO   (United States)

^c Epigenomic Medicine   (United Kingdom)

^d UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

^e MAX PLANCK INSTITUTE OF PSYCHIATRY   (Germany)

^f UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOCORTICOID; FK 506 BINDING PROTEIN; TACROLIMUS BINDING PROTEIN 5;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHRONIC PAIN; CONTROLLED STUDY; DISEASE SEVERITY; DNA METHYLATION; FKBP51 GENE; GENE; GENE EXPRESSION; GENE FUNCTION; GENOTYPE; KNOCKOUT GENE; MALE; MOUSE; NONHUMAN; PAIN THRESHOLD; PRIORITY JOURNAL; PROTEIN FUNCTION; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; SPINAL CORD; WILD TYPE; ANIMAL; C57BL MOUSE; GENE DELETION; GENETICS; INFLAMMATION; METABOLISM; PATHOLOGY; PHYSIOLOGICAL STRESS; POSTERIOR HORN CELL;

ANIMALS; CHRONIC PAIN; DNA METHYLATION; GENE DELETION; GLUCOCORTICOIDS; INFLAMMATION; MALE; MICE, INBRED C57BL; POSTERIOR HORN CELLS; SIGNAL TRANSDUCTION; SPINAL CORD; STRESS, PHYSIOLOGICAL; TACROLIMUS BINDING PROTEINS;

EID: 84958630972     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aab3376     Document Type: Article

References (45)

1. A. S. Zannas, E. B. Binder, Gene-environment interactions at the FKBP5 locus: Sensitive periods, mechanisms and pleiotropism. Genes Brain Behav. 13, 25-37 (2014).
2. T. Klengel, D. Mehta, C. Anacker, M. Rex-Haffner, J. C. Pruessner, C. M. Pariante, T. W. W. Pace, K. B. Mercer, H. S. Mayberg, B. Bradley, C. B. Nemeroff, F. Holsboer, C. M. Heim, K. J. Ressler, T. Rein, E. B. Binder, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat. Neurosci. 16, 33-41 (2013).
3. C. Touma, N. C. Gassen, L. Herrmann, J. Cheung-Flynn, D. R. Büll, I. A. Ionescu, J.-M. Heinzmann, A. Knapman, A. Siebertz, A.-M. Depping, J. Hartmann, F. Hausch, M. V. Schmidt, F. Holsboer, M. Ising, M. B. Cox, U. Schmidt, T. Rein, FK506 binding protein 5 shapes stress responsiveness: Modulation of neuroendocrine reactivity and coping behavior. Biol. Psychiatry 70, 928-936 (2011).
4. J. Hartmann, K. V. Wagner, C. Liebl, S. H. Scharf, X.-D. Wang, M. Wolf, F. Hausch, T. Rein, U. Schmidt, C. Touma, J. Cheung-Flynn, M. B. Cox, D. F. Smith, F. Holsboer, M. B. Müller, M. V. Schmidt, The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress. Neuropharmacology 62, 332-339 (2012).
5. J. C. O'Leary III, S. Dharia, L. J. Blair, S. Brady, A. G. Johnson, M. Peters, J. Cheung-Flynn, M. B. Cox, G. de Erausquin, E. J. Weeber, U. K. Jinwal, C. A. Dickey, A new anti-depressive strategy for the elderly: Ablation of FKBP5/FKBP51. PLOS One 6, e24840 (2011).
6. J. C. Ulirsch, M. A. Weaver, A. V. Bortsov, A. C. Soward, R. A. Swor, D. A. Peak, J. S. Jones, N. K. Rathlev, D. C. Lee, R. M. Domeier, P. L. Hendry, S. A. McLean, No man is an island: Living in a disadvantaged neighborhood influences chronic pain development after motor vehicle collision. Pain 155, 2116-2123 (2014).
7. A. V. Bortsov, J. E. Smith, L. Diatchenko, A. C. Soward, J. C. Ulirsch, C. Rossi, R. A. Swor, W. E. Hauda, D. A. Peak, J. S. Jones, D. Holbrook, N. K. Rathlev, K. A. Foley, D. C. Lee, R. Collette, R. M. Domeier, P. L. Hendry, S. A. McLean, Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure. Pain 154, 1419-1426 (2013).
8. S. M. Géranton, V. Fratto, K. K. Tochiki, S. P. Hunt, Descending serotonergic controls regulate inflammation-induced mechanical sensitivity and methyl-CpG-binding protein 2 phosphorylation in the rat superficial dorsal horn. Mol. Pain 4, 35 (2008).
9. K. K. Tochiki, J. Cunningham, S. P. Hunt, S. M. Géranton, The expression of spinal methyl-CpG-binding protein 2, DNA methyltransferases and histone deacetylases is modulated in persistent pain states. Mol. Pain 8, 14 (2012).
10. S. M. Géranton, C. Morenilla-Palao, S. P. Hunt, A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states. J. Neurosci. 27, 6163-6173 (2007).
11. S. Gaali, A. Kirschner, S. Cuboni, J. Hartmann, C. Kozany, G. Balsevich, C. Namendorf, P. Fernandez-Vizarra, C. Sippel, A. S. Zannas, R. Draenert, E. B. Binder, O. F. X. Almeida, G. Rühter, M. Uhr, M. V. Schmidt, C. Touma, A. Bracher, F. Hausch, Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat. Chem. Biol. 11, 33-37 (2015).
12. T. Jääskeläinen, H. Makkonen, J. J. Palvimo, Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr. Opin. Pharmacol. 11, 326-331 (2011).
13. L. A. Stechschulte, E. R. Sanchez, FKBP51-a selective modulator of glucocorticoid and androgen sensitivity. Curr. Opin. Pharmacol. 11, 332-337 (2011).
14. S. Wang, G. Lim, Q. Zeng, B. Sung, L. Yang, J. Mao, Central glucocorticoid receptors modulate the expression and function of spinal NMDA receptors after peripheral nerve injury. J. Neurosci. 25, 488-495 (2005).
15. S. Wang, G. Lim, Q. Zeng, B. Sung, Y. Ai, G. Guo, L. Yang, J. Mao, Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats. J. Neurosci. 24, 8595-8605 (2004).
16. I. Takasaki, T. Kurihara, H. Saegusa, S. Zong, T. Tanabe, Effects of glucocorticoid receptor antagonists on allodynia and hyperalgesia in mouse model of neuropathic pain. Eur. J. Pharmacol. 524, 80-83 (2005).
17. R. S. Lee, K. L. K. Tamashiro, X. Yang, R. H. Purcell, A. Harvey, V. L. Willour, Y. Huo, M. Rongione, G. S. Wand, J. B. Potash, Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice. Endocrinology 151, 4332-4343 (2010).
18. I. Decosterd, C. J. Woolf, Spared nerve injury: An animal model of persistent peripheral neuropathic pain. Pain 87, 149-158 (2000).
19. + microglia drive neuropathic pain. Nat. Neurosci. 15, 1068-1073 (2012).
20. Y. Lu, B.-C. Jiang, D.-L. Cao, Z.-J. Zhang, X. Zhang, R.-R. Ji, Y.-J. Gao, TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-a and IL-1b signaling. Pain 155, 2618-2629 (2014).
21. T. D. Hinds Jr., S. Ramakrishnan, H. A. Cash, L. A. Stechschulte, G. Heinrich, S. M. Najjar, E. R. Sanchez, Discovery of glucocorticoid receptor-b in mice with a role in metabolism. Mol. Endocrinol. 24, 1715-1727 (2010).
22. L. J. Lewis-Tuffin, J. A. Cidlowski, The physiology of human glucocorticoid receptor b (hGRb) and glucocorticoid resistance. Ann. N. Y. Acad. Sci. 1069, 1-9 (2006).
23. M. Erta, A. Quintana, J. Hidalgo, Interleukin-6, a major cytokine in the central nervous system. Int. J. Biol. Sci. 8, 1254-1266 (2012).
24. R. F. De Jongh, K. C. Vissers, T. F. Meert, L. H. D. J. Booij, C. S. De Deyne, R. J. Heylen, The role of interleukin-6 in nociception and pain. Anesth. Analg. 96, 1096-1103 (2003).
25. N. J. D. Verhoog, A. D. Toit, C. Avenant, J. P. Hapgood, Glucocorticoid-independent repression of tumor necrosis factor (TNF) a-stimulated interleukin (IL)-6 expression by the glucocorticoid receptor: A potential mechanism for protection against an excessive inflammatory response. J. Biol. Chem. 286, 19297-19310 (2011).
26. P. J. Fuller, B. J. Smith, F. M. Rogerson, Cortisol resistance in the New World revisited. Trends Endocrinol. Metab. 15, 296-299 (2004).
27. W. B. Denny, D. L. Valentine, P. D. Reynolds, D. F. Smith, J. G. Scammell, Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology 141, 4107-4113 (2000).
28. G. M. Wochnik, J. Rüegg, G. A. Abel, U. Schmidt, F. Holsboer, T. Rein, FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J. Biol. Chem. 280, 4609-4616 (2005).
29. T. R. Hubler, J. G. Scammell, Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids. Cell Stress Chaperones 9, 243-252 (2004).
30. V. Paakinaho, H. Makkonen, T. Jääskeläinen, J. J. Palvimo, Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. Mol. Endocrinol. 24, 511-525 (2010).
31. Z. Zhou, E. J. Hong, S. Cohen, W.-n. Zhao, H.-y. H. Ho, L. Schmidt, W. G. Chen, Y. Lin, E. Savner, E. C. Griffith, L. Hu, J. A. J. Steen, C. J. Weitz, M. E. Greenberg, Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255-269 (2006).
32. U. A. Nuber, S. Kriaucionis, T. C. Roloff, J. Guy, J. Selfridge, C. Steinhoff, R. Schulz, B. Lipkowitz, H. H. Ropers, M. C. Holmes, A. Bird, Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum. Mol. Genet. 14, 2247-2256 (2005).
33. E. R. Ewald, G. S. Wand, F. Seifuddin, X. Yang, K. L. Tamashiro, J. B. Potash, P. Zandi, R. S. Lee, Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure. Psychoneuroendocrinology 44, 112-122 (2014).
34. D. Cruz-Topete, J. A. Cidlowski, One hormone, two actions: Anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 22, 20-32 (2015).
35. R. H. Oakley, J. A. Cidlowski, The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease. J. Allergy Clin. Immunol. 132, 1033-1044 (2013).
36. S. Sallmann, E. Jüttler, S. Prinz, N. Petersen, U. Knopf, T. Weiser, M. Schwaninger, Induction of interleukin-6 by depolarization of neurons. J. Neurosci. 20, 8637-8642 (2000).
37. S. Beggs, G. Currie, M. W. Salter, M. Fitzgerald, S. M. Walker, Priming of adult pain responses by neonatal pain experience: Maintenance by central neuroimmune activity. Brain 135, 404-417 (2012).
38. S. M. Walker, K. K. Tochiki, M. Fitzgerald, Hindpaw incision in early life increases the hyperalgesic response to repeat surgical injury: Critical period and dependence on initial afferent activity. Pain 147, 99-106 (2009).
39. C. Hermann, J. Hohmeister, S. Demirakça, K. Zohsel, H. Flor, Long-term alteration of pain sensitivity in school-aged children with early pain experiences. Pain 125, 278-285 (2006).
40. M. V. Schmidt, M. Paez-Pereda, F. Holsboer, F. Hausch, The prospect of FKBP51 as a drug target. ChemMedChem 7, 1351-1359 (2012).
41. J. S. Mogil, J. Ritchie, S. G. Sotocinal, S. B. Smith, S. Croteau, D. J. Levitin, A. K. Naumova, Screening for pain phenotypes: Analysis of three congenic mouse strains on a battery of nine nociceptive assays. Pain 126, 24-34 (2006).
42. S. R. Chaplan, F. W. Bach, J. W. Pogrel, J. M. Chung, T. L. Yaksh, Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55-63 (1994).
43. K. Hargreaves, R. Dubner, F. Brown, C. Flores, J. Joris, A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77-88 (1988).
44. C. A. Fairbanks, Spinal delivery of analgesics in experimental models of pain and analgesia. Adv. Drug Deliv. Rev. 55, 1007-1041 (2003).
45. 50's using von Frey thresholds: Impact of Weber's law and log transformation. J. Pain 13, 519-523 (2012).