Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: Evidence from in vitro and animal-based studies

Journal of Musculoskeletal Neuronal Interactions

Volumn 8, Issue 2, 2008, Pages 121-132

  Warden, Stuart J ^a   Haney, E M ^b  

^a INDIANA UNIVERSITY   (United States)

^b OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

Antidepressants; Fluoxetine; Neurotransmitter; Osteoporosis; Prozac

Indexed keywords

DESIPRAMINE; FLUOXETINE; IMIPRAMINE; SEROTONIN ANTAGONIST; SEROTONIN TRANSPORTER; SEROTONIN UPTAKE INHIBITOR; TRICYCLIC ANTIDEPRESSANT AGENT;

BONE DEVELOPMENT; CELL DIFFERENTIATION; CELL PROLIFERATION; CHRONIC STRESS; CORTICAL BONE; DIARRHEA; DRUG EFFECT; GASTROINTESTINAL SYMPTOM; HUMAN; MAJOR DEPRESSION; MECHANOTRANSDUCTION; MOOD DISORDER; NAUSEA; NEUROTRANSMISSION; NONHUMAN; PHYSICAL ACTIVITY; REVIEW; SEROTONINERGIC SYSTEM;

ANIMALS; BONE AND BONES; SEROTONIN; SEROTONIN PLASMA MEMBRANE TRANSPORT PROTEINS; SEROTONIN UPTAKE INHIBITORS;

EID: 51749112868     PISSN: 11087161     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (90)

1. Patel MS, Elefteriou F. The new field of neuroskeletal biology. Calcif Tissue Int 2007;80:337-47.
2. Warden SJ, Bliziotes MM, Wiren KM, Eshleman AJ, Turner CH. Neural regulation of bone and the skeletal effects of serotonin (5-hydroxytryptamine). Mol Cell Endocrinol 2005;242:1-9.
3. Mach DB, Rogers SD, Sabino MC, Luger NM, Schwei MJ, Pomonis JD, Keyser CP, Clohisy DR, Adams DJ, O'Leary P, Mantyh PW. Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience 2002;113:155-66.
4. Baldock PA, Sainsbury A, Allison S, Lin EJ, Couzens M, Boey D, Enriquez R, During M, Herzog H, Gardiner EM. Hypothalamic control of bone formation: distinct actions of leptin and Y2 receptor pathways. J Bone Miner Res 2005;20:1851-7.
5. Baldock PA, Sainsbury A, Couzens M, Enriquez RF, Thomas GP, Gardiner EM, Herzog H. Hypothalamic Y2 receptors regulate bone formation. J Clin Invest 2002;109:915-21.
6. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, hen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100:197-207.
7. Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 2005;434:514-20.
8. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G. Leptin regulates bone formation via the sympathetic nervous system. Cell 2002;111:305-17.
9. Allison SJ, Baldock P, Sainsbury A, Enriquez R, Lee NJ, Lin EJ, Klugmann M, During M, Eisman JA, Li M, Pan LC, Herzog H, Gardiner EM. Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-induced bone loss in adult mice. J Biol Chem 2006;281:23436-44.
10. Sainsbury A, Baldock PA, Schwarzer C, Ueno N, Enriquez RF, Couzens M, Inui A, Herzog H, Gardiner EM. Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Mol Cell Biol 2003;23:5225-33.
11. Offley SC, Guo TZ, Wei T, Clark JD, Vogel H, Lindsey DP, Jacobs CR, Yao W, Lane NE, Kingery WS. Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. J Bone Miner Res 2005;20:257-67.
12. Gu Y, Publicover SJ. Expression of functional metabotropic glutamate receptors in primary cultured rat osteoblasts. Cross-talk with N-methyl-D-aspartate receptors. J Biol Chem 2000;275:34252-9.
13. Mason DJ, Suva LJ, Genever PG, Patton AJ, Steuckle S, Hillam RA, Skerry TM. Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents? Bone 1997;20:199-205.
14. Bliziotes M, McLoughlin S, Gunness M, Fumagalli F, Jones SR, Caron MG. Bone histomorphometric and biomechanical abnormalities in mice homozygous for deletion of the dopamine transporter gene. Bone 2000;26:15-9.
15. Haney EM, Bliziotes MM. Selective serotonin reuptake inhibitors and bone health. Future Rheumatol 2007;2:213-22.
16. Diem SJ, Blackwell TL, Stone KL, Yaffe K, Haney EM, Bliziotes MM, Ensrud KE. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med 2007;167:1240-5.
17. Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, Orwoll E, Bliziotes MM; for the Osteoporotic Fractures in Men Study Group. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med 2007;167:1246-51.
18. Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC, Goltzman D: Canadian Multicentre Osteoporosis Study Research Group. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 2007;167:188-94.
19. Haney EM, Warden SJ. Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from clinical studies. J Musculoskelet Neuronal Interact 2008;8:138-150.
20. Rapport MM, Green AA, Page IH. Serum vasoconstrictor (serotonin). IV. Isolation and characterization. J Biol Chem 1948;176:1243-51.
21. Rapport MM, Green AA, Page IH. Crystalline serotonin. Science 1948;108:329-330.
22. Kroeze WK, Kristiansen K, Roth BL. Molecular biology of serotonin receptors structure and function at the molecular level. Curr Top Med Chem 2002;2:507-28.
23. Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN. Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 2001;92:179-212.
24. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132:397-414.
25. Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J Clin Gastroenterol 2005;39:S184-93.
26. Talley NJ. Serotoninergic neuroenteric modulators. Lancet 2001;358:2061-8.
27. McNicol A, Israels SJ. Platelet dense granules: structure, function and implications for haemostasis. Thromb Res 1999;95:1-18.
28. Kaumann AJ, Levy FO. 5-hydroxytryptamine receptors in the human cardiovascular system. Pharmacol Ther 2006;111:674-706.
29. Ni W, Watts SW. 5-hydroxytryptamine in the cardiovascular system: focus on the serotonin transporter (SERT). Clin Exp Pharmacol Physiol 2006;33:575-83.
30. Egermayer P, Town GI, Peacock AJ. Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension. Thorax 1999;54:161-8.
31. Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol 1994;266:L46-52.
32. Saier MH Jr. A functional-phylogenetic system for the classification of transport proteins. J Cell Biochem 1999;(Suppl.)32-33:84-94.
33. Murphy DL, Lerner A, Rudnick G, Lesch KP. Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv 2004;4:109-23.
34. Zhou FC, Tao-Cheng JH, Segu L, Patel T, Wang Y. Serotonin transporters are located on the axons beyond the synaptic junctions: anatomical and functional evidence. Brain Res 1998;805:241-54.
35. Mann JJ. Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior. Neuropsychopharmacology 1999;21:99S-105S.
36. Meyer JH. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 2007;32:86-102.
37. Stockmeier CA. Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 2003;37:357-73.
38. Arroll B, Macgillivray S, Ogston S, Reid I, Sullivan F, Williams B, Crombie I. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med 2005;3:449-56.
39. Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry 2006;63:1217-23.
40. Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD, Gershon MD. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci 1996;16:2352-64.
41. Gershon MD. 5-HT (serotonin) physiology and related drugs. Curr Opin Gastroenterol 2000;16:113-20.
42. Trindade E, Menon D, Topfer LA, Coloma C. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. CMAJ 1998;159:1245-52.
43. Battaglino R, Fu J, Spate U, Ersoy U, Joe M, Sedaghat L, Stashenko P. Serotonin regulates osteoclast differentiation via its transporter. J Bone Miner Res 2004;19:1420-1431.
44. Bliziotes M, Eshleman A, Burt-Pichat B, Zhang XW, Hashimoto J, Wiren K, Chenu C. Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone 2006;39:1313-21.
45. Bliziotes MM, Eshleman AJ, Zhang X-W, Wiren KM. Neurotransmitter action in osteoblasts: Expression of a functional system for serotonin receptor activation and reuptake. Bone 2001;29:477-486.
46. Gustafsson BI, Thommesen L, Stunes AK, Tommeras K, Westbroek I, Waldum HL, Slordahl K, Tamburstuen MV, Reseland JE, Syversen U. Serotonin and fluoxetine modulate bone cell function in vitro. J Cell Biochem 2006;98:139-51.
47. Hansson SR, Mezey E, Hoffman BJ. Serotonin transporter messenger RNA expression in neural crest-derived structures and sensory pathways of the developing rat embryo. Neuroscience 1999;89:243-65.
48. Lauder JM, Zimmerman EF. Sites of serotonin uptake in epithelia of the developing mouse palate, oral cavity, and face: possible role in morphogenesis. J Craniofac Genet Dev Biol 1988;8:265-76.
49. Shuey DL, Sadler TW, Lauder JM. Serotonin as a regulator of craniofacial morphogenesis: site specific malformations following exposure to serotonin uptake inhibitors. Teratology 1992;46:367-78.
50. Moiseiwitsch JR. The role of serotonin and neurotransmitters during craniofacial development. Crit Rev Oral Biol Med 2000;11:230-9.
51. Erspamer V. Occurrence of indolealkylamines in nature. In: Erspamer V, editor. Handbook of Experimental Pharmacology: 5-hydroxytryptamine and Related Indolealkylamines. New York: Springer, 1966:132-181.
52. Anderson GM, Feibel FC, Cohen DJ. Determination of serotonin in whole blood, platelet-rich plasma, platelet-poor plasma and plasma ultrafiltrate. Life Sci 1987;40:1063-70.
53. Saper CB. Brain stem modulation of sensation, movement, and consciousness. In: Kandel ER, Schwartz JH, Jessel TM, editors. Principles of Neural Science. 4th ed. New York: McGraw Hill, 2000:889-909.
54. Grahame-Smith DG. Tryptophan hydroxylation in brain. Biochem Biophys Res Commun 1964;16:586-92.
55. Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 2003;66:1673-80.
56. Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003;299:76.
57. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002;71:533-54.
58. Fink KB, Gothert M. 5-HT receptor regulation of neurotransmitter release. Pharmacol Rev 2007;59:360-417.
59. Locker M, Bitard J, Collet C, Poliard A, Mutel V, Launay JM, Kellermann O. Stepwise control of osteogenic differentiation by 5-HT(2B) receptor signaling: nitric oxide production and phospholipase A2 activation. Cell Signal 2006;18:628-39.
60. Westbroek I, van der Plas A, de Rooij KE, Klein-Nulend J, Nijweide PJ. Expression of serotonin receptors in bone. J Biol Chem 2001;276:28961-8.
61. Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC. The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation. FASEB J 2008;22:418-27.
62. Liedert A, Kaspar D, Blakytny R, Claes L, Ignatius A. Signal transduction pathways involved in mechanotransduction in bone cells. Biochem Biophys Res Commun 2006;349:1-5.
63. National Institutes of Health. Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement 2000;17:1-45.
64. Battaglino R, Vokes M, Schulze-Spate U, Sharma A, Graves D, Kohler T, Müller R, Yoganathan S, Stashenko P. Fluoxetine treatment increases trabecular bone formation in mice. J Cell Biochem 2007;100:1387-94.
65. Gustafsson BI, Westbroek I, Waarsing JH, Waldum H, Solligard E, Brunsvik A, Dimmen S, van Leeuwen JP, Weinans H, Syversen U. Long-term serotonin administration leads to higher bone mineral density, affects bone architecture, and leads to higher femoral bone stiffness in rats. J Cell Biochem 2006;97:1283-91.
66. Yirmiya R, Goshen I, Bajayo A, Kreisel T, Feldman S, Tam J, Trembovler V, Csernus V, Shohami E, Bab I. Depression induces bone loss through stimulation of the sympathetic nervous system. Proc Natl Acad Sci U S A 2006;103:16876-81.
67. Bonnet N, Bernard P, Beaupied H, Bizot JC, Trovero F, Courteix D, Benhamou CL. Various effects of antidepressant drugs on bone microarchitectecture, mechanical properties and bone remodeling. Toxicol Appl Pharmacol 2007;221:111-8.
68. Warden SJ, Nelson IR, Fuchs RK, Bliziotes MM, Turner CH. Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen. Menopause (in press).
69. Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner CH. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 2005;146:685-93.
70. Westbroek I, Waarsing JH, van Leeuwen JP, Waldum H, Reseland JE, Weinans H, Syversen U, Gustafsson BI. Long-term fluoxetine administration does not result in major changes in bone architecture and strength in growing rats. J Cell Biochem 2007;101:360-8.
71. Gustafsson BI, Tommeras K, Nordrum I, Loennechen JP, Brunsvik A, Solligard E, Fossmark R, Bakke I, Syversen U, Waldum H. Long-term serotonin administration induces heart valve disease in rats. Circulation 2005;111:1517-22.
72. Leysen JE. 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord 2004;3(1):11-26.
73. Nebigil CG, Choi DS, Dierich A, Hickel P, Le Meur M, Messaddeq N, Launay JM, Maroteaux L. Serotonin 2B receptor is required for heart development. Proc Natl Acad Sci U S A 2000;97:9508-13.
74. Turner CH, Robling AG, Duncan RL, Burr DB. Do bone cells behave like a neuronal network? Calcif Tissue Int 2002;70:435-242.
75. Holmes A, Yang RJ, Murphy DL, Crawley JN. Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology 2002;27:914-23.
76. Kalueff AV, Fox MA, Gallagher PS, Murphy DL. Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice. Genes Brain Behav 2007;6:389-400.
77. Kalueff AV, Jensen CL, Murphy DL. Locomotory patterns, spatiotemporal organization of exploration and spatial memory in serotonin transporter knockout mice. Brain Res 2007;1169:87-97.
78. Chen JJ, Li Z, Pan H, Murphy DL, Tamir H, Koepsell H, Gershon MD. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: abnormal intestinal motility and the expression of cation transporters. J Neurosci 2001;21:6348-61.
79. Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mössner R, Westphal H, Lesch KP. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient mice. Mol Pharmacol 1998;53:649-55.
80. Hanley NR, Van de Kar LD. Serotonin and the neuroendocrine regulation of the hypothalamic-pituitary-adrenal axis in health and disease. Vitam Horm 2003;66:189-255.
81. Weber CC, Eckert GP, Muller WE. Effects of antidepressants on the brain/ plasma distribution of corticosterone. Neuropsychopharmacology 2006;31:2443-8.
82. Tjurmina OA, Armando I, Saavedra JM, Goldstein DS, Murphy DL. Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology 2002;143:4520-6.
83. Tjurmina OA, Armando I, Saavedra JM, Li Q, Murphy DL. Life-long serotonin reuptake deficiency results in complex alterations in adrenomedullary responses to stress. Ann N Y Acad Sci 2004;1018:99-104.
84. Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 2003;4:1002-12.
85. Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159:1889-95.
86. Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, Donnenfeld A, McCormack M, Leen-Michell M, Woodland C, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA 1993;269:2246-8.
87. Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry 2002;159:2055-61.
88. Ferguson VL, Greenberg AR, Bateman TA, Ayers RA, Simske SJ. The effects of age and dietary restriction without nutritional supplementation on whole bone structural properties in C57BL/6J mice. Biomed Sci Instrum 1999;35:85-91.
89. Dulawa SC, Holick KA, Gundersen B, Hen R. Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology 2004;29:1321-30.
90. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 1997;283:1305-22.