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Circadian Regulation of Bone

  • Sifat Maria
  • Paula A. Witt-Enderby
Chapter
Part of the Healthy Ageing and Longevity book series (HAL, volume 7)

Abstract

The demands of modern society are posing serious effects on our bone health. People are working longer hours, working through the night, getting less sleep, and eating at irregular hours. This is causing more stress and less time to spend outdoors. All of these factors are contributing to circadian disruption “in general” but more importantly to circadian disruption of bone rhythms. Bone metabolism displays circadian variation that is coincident with clock rhythms in bone, with the light/dark cycle and with circulating melatonin levels. Light exposure at night, shift work, and poor quality sleep can lead to weakened bones attributed, in part, to altered clock rhythms in bone and to changes in circulating melatonin and cortisol rhythms in the body. The intent of this review is not to describe bone metabolism “in general” and then to discuss the effect of melatonin in these processes. There are many reviews on this subject matter described throughout the chapter. Rather, the focus of this chapter is to describe clock gene expression and function in bone and how their rhythms impact on osteoblast and osteoclast activity and differentiation and on bone metabolism; and then discuss variables that lead to circadian disruption of bone rhythms and describe ways to maintain healthy bone in a society that continually promotes circadian disruption.

Keywords

Bone rhythms Melatonin Osteoclasts Osteoblasts Shift work Circadian disruption 

References

  1. Amstrup AK, Sikjaer T, Heickendorff L, Mosekilde L, Rejnmark L (2015) Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. J Pineal Res 59:221–229CrossRefPubMedGoogle Scholar
  2. Aoshima H, Kushida K, Takahashi M, Ohishi T, Hoshino H, Suzuki M, Inoue T (1998) Circadian variation of urinary type I collagen crosslinked C-telopeptide and free and peptide-bound forms of pyridinium crosslinks. Bone 22:73–78CrossRefPubMedGoogle Scholar
  3. Azeddine B, Letellier K, da Wang S, Moldovan F, Moreau A (2007) Molecular determinants of melatonin signaling dysfunction in adolescent idiopathic scoliosis. Clin Orthop Relat Res 462:45–52Google Scholar
  4. Bedrosian TA, Fonken LK, Nelson RJ (2016) Endocrine effects of circadian disruption. Annu Rev Physiol 78:109–131CrossRefPubMedGoogle Scholar
  5. Blask DE, Brainard GC, Dauchy RT, Hanifin JP, Davidson LK, Krause JA, Sauer LA, Rivera-Bermudez MA, Dubocovich ML, Jasser SA, Lynch DT, Rollag MD, Zalatan F (2005) Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res 65:11174–11184CrossRefPubMedGoogle Scholar
  6. Bollen AM, Martin MD, Leroux BG, Eyre DR (1995) Circadian variation in urinary excretion of bone collagen cross-links. J Bone Miner Res 10:1885–1890CrossRefPubMedGoogle Scholar
  7. Bonmati-Carrion MA, Arguelles-Prieto R, Martinez-Madrid MJ, Reiter R, Hardeland R, Rol MA, Madrid JA (2014) Protecting the melatonin rhythm through circadian healthy light exposure. Int J Mol Sci 15:23448–23500CrossRefPubMedPubMedCentralGoogle Scholar
  8. Cagnacci A, Soldani R, Yen SS (1995) Melatonin enhances cortisol levels in aged but not young women. Eur J Endocrinol 133:691–695CrossRefPubMedGoogle Scholar
  9. Cagnacci A, Soldani R, Yen SS (1997) Melatonin enhances cortisol levels in aged women: reversible by estrogens. J Pineal Res 22:81–85CrossRefPubMedGoogle Scholar
  10. Chung S, Son GH, Kim K (2011) Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. Biochim Biophys Acta 1812:581–591CrossRefPubMedGoogle Scholar
  11. Cole RJ, Kripke DF, Wisbey J, Mason WJ, Gruen W, Hauri PJ, Juarez S (1995) Seasonal variation in human illumination exposure at two different latitudes. J Biol Rhythms 10:324–334CrossRefPubMedGoogle Scholar
  12. Diffey BL (2011) An overview analysis of the time people spend outdoors. Br J Dermatol 164:848–858CrossRefPubMedGoogle Scholar
  13. Eastell R, Calvo MS, Burritt MF, Offord KP, Russell RG, Riggs BL (1992) Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. J Clin Endocrinol Metab 74:487–494PubMedGoogle Scholar
  14. Egermann M, Gerhardt C, Barth A, Maestroni GJ, Schneider E, Alini M (2011) Pinealectomy affects bone mineral density and structure-an experimental study in sheep. BMC Musculoskelet Disord 12:1CrossRefGoogle Scholar
  15. Feskanich D, Hankinson SE, Schernhammer ES (2009) Nightshift work and fracture risk: the Nurses’ Health Study. Osteopor Int 20:537–542CrossRefGoogle Scholar
  16. Fjelldal PG, Grotmol S, Kryvi H, Gjerdet NR, Taranger GL, Hansen T, Porter MJ, Totland GK (2004) Pinealectomy induces malformation of the spine and reduces the mechanical strength of the vertebrae in Atlantic salmon, Salmo salar. J Pineal Res 36:132–139CrossRefPubMedGoogle Scholar
  17. Fu L, Patel MS, Bradley A, Wagner EF, Karsenty G (2005) The molecular clock mediates leptin-regulated bone formation. Cell 122:803–815CrossRefPubMedGoogle Scholar
  18. Gery S, Virk RK, Chumakov K, Yu A, Koeffler HP (2007) The clock gene Per2 links the circadian system to the estrogen receptor. Oncogene 26:7916–7920CrossRefPubMedGoogle Scholar
  19. Greenspan SL, Dresner-Pollak R, Parker RA, London D, Ferguson L (1997) Diurnal variation of bone mineral turnover in elderly men and women. Calcif Tissue Int 60:419–423CrossRefPubMedGoogle Scholar
  20. Gu X, Xing L, Shi G, Liu Z, Wang X, Qu Z, Wu X, Dong Z, Gao X, Liu G, Yang L, Xu Y (2012) The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis. Cell Death Differ 19:397–405CrossRefPubMedGoogle Scholar
  21. Heshmati HM, Riggs BL, Burritt MF, McAlister CA, Wollan PC, Khosla S (1998) Effects of the circadian variation in serum cortisol on markers of bone turnover and calcium homeostasis in normal postmenopausal women. J Clin Endocrinol Metab 83:751–756PubMedGoogle Scholar
  22. Hubert M, Dumont M, Paquet J (1998) Seasonal and diurnal patterns of human illumination under natural conditions. Chronobiol Int 15:59–70CrossRefGoogle Scholar
  23. Iguichi H, Kato KI, Ibayashi H (1982) Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metab 55:27–29CrossRefPubMedGoogle Scholar
  24. Inouye S-I, Kawamura H (1979) Persistence of circadian rhythmicity in a mammalian hypothalamic “island” containing the suprachiasmatic nucleus. Proc Natl Acad Sci 76:5962–5966CrossRefPubMedPubMedCentralGoogle Scholar
  25. Ishida A, Mutoh T, Ueyama T, Bando H, Masubuchi S, Nakahara D, Tsujimoto G, Okamura H (2005) Light activates the adrenal gland: timing of gene expression and glucocorticoid release. Cell Metab 2:297–307CrossRefPubMedGoogle Scholar
  26. Jung-Hynes B, Huang W, Reiter RJ, Ahmad N (2010) Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells. J Pineal Res 49:60–68PubMedPubMedCentralGoogle Scholar
  27. Kennaway DJ, Voultsios A, Varcoe TJ, Moyer RW (2002) Melatonin in mice: rhythms, response to light, adrenergic stimulation, and metabolism. Am J Physiol Regul Integr Comp Physiol 282:R358–R365CrossRefPubMedGoogle Scholar
  28. Kim BK, Choi YJ, Chung Y-S (2013) Other than daytime working is associated with lower bone mineral density: the Korea National Health and Nutrition Examination Survey 2009. Calcif Tissue Int 93:495–501CrossRefPubMedGoogle Scholar
  29. Komoto S, Kondo H, Fukuta O, Togari A (2012) Comparison of β-adrenergic and glucocorticoid signaling on clock gene and osteoblast-related gene expressions in human osteoblast. Chronobiol Int 29:66–74CrossRefPubMedGoogle Scholar
  30. Kondo H, Togari A (2015) Circadian regulation of bone metabolism by β-adrenergic signaling, glucocorticoids, and clock genes. J Oral Biosci 57:9–13CrossRefGoogle Scholar
  31. Kono H, Machida M, Saito M, Nishiwaki Y, Kato H, Hosogane N, Chiba K, Miyamoto T, Matsumoto M, Toyama Y (2011) Mechanism of osteoporosis in adolescent idiopathic scoliosis: experimental scoliosis in pinealectomized chickens. J Pineal Res 51:387–393CrossRefPubMedGoogle Scholar
  32. Kotlarczyk MP, Lassila HC, O’Neil CK, D’Amico F, Enderby LT, Witt-Enderby PA, Balk JL (2012) Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res 52:414–426CrossRefPubMedGoogle Scholar
  33. Koyama H, Nakade O, Takada Y, Kaku T, Lau KH (2002) Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res 17:1219–1229CrossRefPubMedGoogle Scholar
  34. Lesniewska B, Nowak M, Nussdorfer GG, Malendowicz LK (1990) Sex-dependent effect of melatonin on the secretory activity of rat and hamster adrenal gland in vitro. Life Sci 47:241–245CrossRefPubMedGoogle Scholar
  35. Lockley SW (2007) Visual impairment and circadiam rhythm disorders. Dialogues Clin Neurosci 9:301–314PubMedPubMedCentralGoogle Scholar
  36. Machida M, Dubousset J, Imamura Y, Iwaya T, Yamada T, Kimura J (1995) Role of melatonin deficiency in the development of scoliosis in pinealectomised chickens. J Bone Joint Surg Br 77:134–138PubMedGoogle Scholar
  37. Maria S, Witt-Enderby PA (2014) Melatonin effects on bone: potential use for the prevention and treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone-grafting procedures. J Pineal Res 56:115–125CrossRefPubMedGoogle Scholar
  38. Maronde E, Schilling AF, Seitz S, Schinke T, Schmutz I, van der Horst G, Amling M, Albrecht U (2010) The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation. PLoS ONE 5:e11527CrossRefPubMedPubMedCentralGoogle Scholar
  39. Min H-Y, Kim K-M, Wee G, Kim E-J, Jang W-G (2016) Bmal1 induces osteoblast differentiation via regulation of BMP2 expression in MC3T3-E1 cells. Life Sci 162:41Google Scholar
  40. Moreau A, da Wang S, Forget S, Azeddine B, Angeloni D, Fraschini F, Labelle H, Poitras B, Rivard CH, Grimard G (2004) Melatonin signaling dysfunction in adolescent idiopathic scoliosis. Spine 29:1772–1781Google Scholar
  41. Navara KJ, Nelson RJ (2007) The dark side of light at night: physiological, epidemiological, and ecological consequences. J Pineal Res 43:215–224CrossRefPubMedGoogle Scholar
  42. Nielsen HK, Laurberg P, Brixen K, Mosekilde L (1991) Relations between diurnal variations in serum osteocalcin, cortisol, parathyroid hormone, and ionized calcium in normal individuals. Acta Endocrinol 124:391–398PubMedGoogle Scholar
  43. Novakova M, Nevsimalova S, Prihodova I, Sladek M, Sumova A (2012) Alteration of the circadian clock in children with Smith-Magenis syndrome. J Clin Endocrinol Metab 97:E312–E318CrossRefPubMedGoogle Scholar
  44. Ogle TF, Kitay JI (1978) In vitro effects of melatonin and serotonin on adrenal steroidogenesis. Proc Soc Exp Biol Med 157:103–105CrossRefPubMedGoogle Scholar
  45. Ohayon MM, Milesi C (2016) Artificial outdoor nighttime lights associate with altered sleep behavior in the American general population. Sleep 39:1311Google Scholar
  46. Oishi K, Amagai N, Shirai H, Kadota K, Ohkura N, Ishida N (2005) Genome-wide expression analysis reveals 100 adrenal gland-dependent circadian genes in the mouse liver. DNA Res 12:191–202CrossRefPubMedGoogle Scholar
  47. Oliveri B, Pellegrini GG, di Gregorio S, Wittich A, Cardinali DP, Zeni SN (2008) Daily rhythm in bone resorption in humans: preliminary observations on the effect of hypoparathyroidism or blindness. Biol Rhythm Res 39:13–19CrossRefGoogle Scholar
  48. Ostrowska Z, Kos-Kudla B, Marek B, Swietochowska E, Gorski J (2001) Assessment of the relationship between circadian variations of salivary melatonin levels and type I collagen metabolism in postmenopausal obese women. Neuro Endocrinol Lett 22:121–127PubMedGoogle Scholar
  49. Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D (2003a) Influence of lighting conditions on daily rhythm of bone metabolism in rats and possible involvement of melatonin and other hormones in this process. Endocr Regul 37:163–174PubMedGoogle Scholar
  50. Ostrowska Z, Kos-Kudla B, Nowak M, Swietochowska E, Marek B, Gorski J, Kajdaniuk D, Wolkowska K (2003b) The relationship between bone metabolism, melatonin and other hormones in sham-operated and pinealectomized rats. Endocr Regul 37:211–224PubMedGoogle Scholar
  51. Oyama J, Murai I, Kanazawa K, Machida M (2006) Bipedal ambulation induces experimental scoliosis in C57BL/6 J mice with reduced plasma and pineal melatonin levels. J Pineal Res 40:219–224CrossRefPubMedGoogle Scholar
  52. Park KH, Kang JW, Lee EM, Kim JS, Rhee YH, Kim M, Jeong SJ, Park YG, Kim SH (2011) Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways. J Pineal Res 51:187–194CrossRefPubMedGoogle Scholar
  53. Potocki L, Glaze D, Tan DX, Park SS, Kashork CD, Shaffer LG, Reiter RJ, Lupski JR (2000) Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J Med Genet 37:428–433CrossRefPubMedPubMedCentralGoogle Scholar
  54. Ptitsyn AA, Zvonic S, Conrad SA, Scott LK, Mynatt RL, Gimble JM (2006) Circadian clocks are resounding in peripheral tissues. PLoS Comput Biol 2:e16CrossRefPubMedPubMedCentralGoogle Scholar
  55. Quevedo I, Zuniga AM (2010) Low bone mineral density in rotating-shift workers. J Clin Densitom 13:467–469CrossRefPubMedGoogle Scholar
  56. Radio NM, Doctor JS, Witt-Enderby PA (2006) Melatonin enhances alkaline phosphatase activity in differentiating human adult mesenchymal stem cells grown in osteogenic medium via MT2 melatonin receptors and the MEK/ERK (1/2) signaling cascade. J Pineal Res 40:332–342CrossRefPubMedGoogle Scholar
  57. Richter HG, Torres-Farfan C, Garcia-Sesnich J, Abarzua-Catalan L, Henriquez MG, Alvarez-Felmer M, Gaete F, Rehren GE, Seron-Ferre M (2008) Rhythmic expression of functional MT1 melatonin receptors in the rat adrenal gland. Endocrinology 149:995–1003CrossRefPubMedGoogle Scholar
  58. Robinson LJ, Yaroslavskiy BB, Griswold RD, Zadorozny EV, Guo L, Tourkova IL, Blair HC (2009) Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-alpha with BCAR1 and Traf6. Exp Cell Res 315:1287–1301CrossRefPubMedPubMedCentralGoogle Scholar
  59. Roth JA, Kim BG, Lin WL, Cho MI (1999) Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem 274:22041–22047CrossRefPubMedGoogle Scholar
  60. Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM (1986) Human melatonin production decreases with age. J Pineal Res 3:379–388CrossRefPubMedGoogle Scholar
  61. Sadat-Ali M, Al-Habdan I, Al-Othman A (2000) Adolescent idiopathic scoliosis. Is low melatonin a cause? Joint Bone Spine 67:62–64PubMedGoogle Scholar
  62. Saintier D, Khanine V, Uzan B, Ea HK, de Vernejoul MC, Cohen-Solal ME (2006) Estradiol inhibits adhesion and promotes apoptosis in murine osteoclasts in vitro. J Steroid Biochem Mol Biol 99:165–173CrossRefPubMedGoogle Scholar
  63. Samsa WE, Vasanji A, Midura RJ, Kondratov RV (2016) Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype. Bone 84:194–203CrossRefPubMedPubMedCentralGoogle Scholar
  64. Schlemmer A, Hassager C, Jensen SB, Christiansen C (1992) Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women. J Clin Endocrinol Metab 74:476–480PubMedGoogle Scholar
  65. Seifert-Klauss V, Prior JC (2010) Progesterone and bone: actions promoting bone health in women. J Osteoporos 2010:845180CrossRefPubMedPubMedCentralGoogle Scholar
  66. Sethi S, Radio NM, Kotlarczyk MP, Chen C, Wei Y, Jockers R, Witt-Enderby PA (2010) Determination of the minimal melatonin exposure required to induce osteoblast differentiation from human mesenchymal stem cells and these effects on downstream signaling pathways. J Pineal Res 49:222–238CrossRefPubMedGoogle Scholar
  67. Sewerynek E, Lewinski A (1989) Melatonin inhibits mitotic activity of adrenocortical cells in vivo and in organ culture. J Pineal Res 7:1–12CrossRefPubMedGoogle Scholar
  68. Silver R, Lesauter J, Tresco PA, Lehman MN (1996) A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382:810–813CrossRefPubMedGoogle Scholar
  69. Smolensky MH, Sackett-Lundeen LL, Portaluppi F (2015) Nocturnal light pollution and underexposure to daytime sunlight: complementary mechanisms of circadian disruption and related diseases. Chronobiol Int 32:1029–1048CrossRefPubMedGoogle Scholar
  70. Srivastava S, Toraldo G, Weitzmann MN, Cenci S, Ross FP, Pacifici R (2001) Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation. J Biol Chem 276:8836–8840CrossRefPubMedGoogle Scholar
  71. Stevens RG (2006) Artificial lighting in the industrialized world: circadian disruption and breast cancer. Cancer Causes Control 17:501–507CrossRefPubMedGoogle Scholar
  72. Suzuki N, Hattori A (2002) Melatonin suppresses osteoclastic and osteoblastic activities in the scales of goldfish. J Pineal Res 33:253–258CrossRefPubMedGoogle Scholar
  73. Turgut M, Kaplan S, Turgut AT, Aslan H, Guvenc T, Cullu E, Erdogan S (2005) Morphological, stereological and radiological changes in pinealectomized chicken cervical vertebrae. J Pineal Res 39:392–399CrossRefPubMedGoogle Scholar
  74. Uebelhart D, Schlemmer A, Johansen JS, Gineyts E, Christiansen C, Delmas PD (1991) Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 72:367–373CrossRefPubMedGoogle Scholar
  75. Waldhauser F, Weiszenbacher G, Frisch H, Zeitlhuber U, Waldhauser M, Wurtman RJ (1984) Fall in nocturnal serum melatonin during prepuberty and pubescence. Lancet 1:362–365CrossRefPubMedGoogle Scholar
  76. Wang K, Wu Y, Yang Y, Chen J, Zhang D, Hu Y, Liu Z, Xu J, Shen Q, Zhang N, Mao X, Liu C (2015) The associations of bedtime, nocturnal, and daytime sleep duration with bone mineral density in pre- and post-menopausal women. Endocrine 49:538–548CrossRefPubMedGoogle Scholar
  77. Witt-Enderby PA, Slater JP, Johnson NA, Bondi CD, Dodda BR, Kotlarczyk MP, Clafshenkel WP, Sethi S, Higginbotham S, Rutkowski JL, Gallagher KM, Davis VL (2012) Effects on bone by the light/dark cycle and chronic treatment with melatonin and/or hormone replacement therapy in intact female mice. J Pineal Res 53:374Google Scholar
  78. Yim AP, Yeung HY, Sun G, Lee KM, Ng TB, Lam TP, Ng BK, Qiu Y, Moreau A, Cheng JC (2013) Abnormal skeletal growth in adolescent idiopathic scoliosis is associated with abnormal quantitative expression of melatonin receptor, MT2. Int J Mol Sci 14:6345–6358CrossRefPubMedPubMedCentralGoogle Scholar
  79. Zaminy A, Ragerdi Kashani I, Barbarestani M, Hedayatpour A, Mahmoudi R, Farzaneh Nejad A (2008) Osteogenic differentiation of rat mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells: melatonin as a differentiation factor. Iran Biomed J 12:133–141Google Scholar
  80. Zawilska JB, Skene DJ, Arendt J (2009) Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol Rep 61:383–410CrossRefPubMedGoogle Scholar
  81. Zeitzer JM, Duffy JF, Lockley SW, Dijk DJ, Czeisler CA (2007) Plasma melatonin rhythms in young and older humans during sleep, sleep deprivation, and wake. Sleep 30:1437–1443CrossRefPubMedPubMedCentralGoogle Scholar
  82. Zhang L, Su P, Xu C, Chen C, Liang A, Du K, Peng Y, Huang D (2010) Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARgamma expression and enhancing Runx2 expression. J Pineal Res 49:364–372CrossRefPubMedGoogle Scholar
  83. Zhou JN, Liu RY, van Heerikhuize J, Hofman MA, Swaab DF (2003) Alterations in the circadian rhythm of salivary melatonin begin during middle-age. J Pineal Res 34:11–16CrossRefPubMedGoogle Scholar
  84. Zvonic S, Ptitsyn AA, Conrad SA, Scott LK, Floyd ZE, Kilroy G, Wu X, Goh BC, Mynatt RL, Gimble JM (2006) Characterization of peripheral circadian clocks in adipose tissues. Diabetes 55:962–970CrossRefPubMedGoogle Scholar
  85. Zvonic S, Ptitsyn AA, Kilroy G, Wu X, Conrad SA, Scott LK, Guilak F, Pelled G, Gazit D, Gimble JM (2007) Circadian oscillation of gene expression in murine calvarial bone. J Bone Miner Res 22:357–365CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Division of Pharmaceutical, Administrative and Social Sciences, School of PharmacyDuquesne UniversityPittsburghUSA
  2. 2.Division of Pharmaceutical Sciences, School of PharmacyDuquesne UniversityPittsburghUSA

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