Current Osteoporosis Reports

, Volume 16, Issue 2, pp 130–137 | Cite as

Good, Bad, or Ugly: the Biological Roles of Bone Marrow Fat

  • Lakshman Singh
  • Sonia Tyagi
  • Damian Myers
  • Gustavo Duque
Bone Marrow and Adipose Tissue (G Duque and B Lecka-Czernik, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Bone Marrow and Adipose Tissue

Abstract

Purpose of Review

Bone marrow fat expresses mixed characteristics, which could correspond to white, brown, and beige types of fat. Marrow fat could act as either energy storing and adipokine secreting white fat or as a source of energy for hematopoiesis and bone metabolism, thus acting as brown fat. However, there is also a negative interaction between marrow fat and other elements of the bone marrow milieu, which is known as lipotoxicity. In this review, we will describe the good and bad roles of marrow fat in the bone, while focusing on the specific components of the negative effect of marrow fat on bone metabolism.

Recent Findings

Lipotoxicity in the bone is exerted by bone marrow fat through the secretion of adipokines and free fatty acids (FFA) (predominantly palmitate). High levels of FFA found in the bone marrow of aged and osteoporotic bone are associated with decreased osteoblastogenesis and bone formation, decreased hematopoiesis, and increased osteoclastogenesis. In addition, FFA such as palmitate and stearate induce apoptosis and dysfunctional autophagy in the osteoblasts, thus affecting their differentiation and function.

Summary

Regulation of marrow fat could become a therapeutic target for osteoporosis. Inhibition of the synthesis of FFA by marrow fat could facilitate osteoblastogenesis and bone formation while affecting osteoclastogenesis. However, further studies testing this hypothesis are still required.

Keywords

Lipotoxicity Osteoporosis Fatty acids Adipokines Palmitate Apoptosis 

Notes

Compliance with Ethical Standards

Conflict of Interest

Lackshman Singh, Sonia Tyagi, Damian Myers, and Gustavo Duque declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Tamma R, Ribatti D. Bone niches, hematopoietic stem cells, and vessel formation. Int J Mol Sci. 2017;18(1):151.Google Scholar
  2. 2.
    Craft CS, Scheller EL. Evolution of the marrow adipose tissue microenvironment. Calcif Tissue Int. 2017;100:461–75.CrossRefPubMedGoogle Scholar
  3. 3.
    Smith JNP, Calvi LM. Concise review: current concepts in bone marrow microenvironmental regulation of hematopoietic stem and progenitor cells. Stem Cells. 2013;31:1044–50.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    • Hardouin P, Rharass T, Lucas S. Bone marrow adipose tissue: to be or not to be a typical adipose tissue? Front Endocrinol (Lausanne). 2016;7:85. Interesting and relevant review on the biology of marrow fat. Google Scholar
  5. 5.
    Paccou J, Hardouin P, Cotten A, Penel G, Cortet B. The role of bone marrow fat in skeletal health: usefulness and perspectives for clinicians. J Clin Endocrinol Metab. 2015;100:3613–21.CrossRefPubMedGoogle Scholar
  6. 6.
    •• Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank AM, Bocian C, et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20:771–84. Excellent report describing the effect of marrow fat on hematopoiesis and bone metabolism. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kawai M, de Paula FJA, Rosen CJ. New insights into osteoporosis: the bone–fat connection. J Int Med. 2012;272:317–29.CrossRefGoogle Scholar
  8. 8.
    Duque G. Bone and fat connection in aging bone. Curr Opin Rheumatol. 2008;20:429–34.CrossRefPubMedGoogle Scholar
  9. 9.
    Sheu Y, Cauley JA. The role of bone marrow and visceral fat on bone metabolism. Curr Osteoporos Rep. 2011;9:67–75.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hardouin P, Marie PJ, Rosen CJ. New insights into bone marrow adipocytes: report from the First European Meeting on Bone Marrow Adiposity (BMA 2015). Bone. 2016;93:212–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Hardouin P, Pansini V, Cortet B. Bone marrow fat. Joint Bone Spine. 2014;81:313–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Sepe A, Tchkonia T, Thomou T, Zamboni M, Kirkland JL. Aging and regional differences in fat cell progenitors—a mini-review. Gerontology. 2011;57:66–75.CrossRefPubMedGoogle Scholar
  13. 13.
    Ng A, Duque G. Osteoporosis as a lipotoxic disease. IBMS BoneKEy. 2010;7:108–23.CrossRefGoogle Scholar
  14. 14.
    Krings A, Rahman S, Huang S, Lu Y, Czernik PJ, Lecka-Czernik B. Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes. Bone. 2012;50:546–52.CrossRefPubMedGoogle Scholar
  15. 15.
    Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252–63.CrossRefPubMedGoogle Scholar
  16. 16.
    Park A, Kim WK, Bae KH. Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. World J Stem Cells. 2014;6:33–42.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hany TF, Gharehpapagh E, Kamel EM, Buck A, Himms-Hagen J, von Schulthess GK. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging. 2002;29:1393–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Rogers NH. Brown adipose tissue during puberty and with aging. Ann Med. 2015;47:142–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Peirce V, Carobbio S, Vidal-Puig A. The different shades of fat. Nature. 2014;510:76–83.CrossRefPubMedGoogle Scholar
  20. 20.
    Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.CrossRefPubMedGoogle Scholar
  21. 21.
    • Sulston RJ, Cawthorn WP. Bone marrow adipose tissue as an endocrine organ: close to the bone? Horm Mol Biol Clin Investig. 2016;28:21–38. Good review on fat and bone interactions. PubMedGoogle Scholar
  22. 22.
    Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front Endocrinol. 2016;7:30.CrossRefGoogle Scholar
  23. 23.
    Cawthorn WP, Scheller EL, Parlee SD, Pham HA, Learman BS, Redshaw CMH, et al. Expansion of bone marrow adipose tissue during caloric restriction is associated with increased circulating glucocorticoids and not with hypoleptinemia. Endocrinology. 2016;157:508–21.CrossRefPubMedGoogle Scholar
  24. 24.
    Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM. Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. Crit Rev Eukaryot Gene Expr. 2009;19:109–24.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone. 2012;50:534–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Scheller EL, Rosen CJ. What’s the matter with MAT? Marrow adipose tissue, metabolism, and skeletal health. Ann N Y Acad Sci. 2014;1311:14–30.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    •• Scheller EL, Doucette CR, Learman BS, Cawthorn WP, Khandaker S, Schell B, et al. Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. Nat Commun. 2015;6:7808. Excellent report on regional distribution of marrow fat. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    •• Devlin MJ, Rosen CJ. The bone–fat interface: basic and clinical implications of marrow adiposity. Lancet Diabetes Endocrinol. 2015;3:141–7. Comprehensive review on the role of marrow fat in health and disease. CrossRefPubMedGoogle Scholar
  29. 29.
    Rahman S, Lu Y, Czernik PJ, Rosen CJ, Enerback S, Lecka-Czernik B. Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton. Endocrinology. 2013;154:2687–701.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Carobbio S, Pellegrinelli V, Vidal-Puig A. Adipose tissue function and expandability as determinants of lipotoxicity and the metabolic syndrome. Adv Exp Med Biol. 2017;960:161–96.CrossRefPubMedGoogle Scholar
  31. 31.
    Unger RH. Lipotoxic diseases. Annu Rev Med. 2002;53:319–36.CrossRefPubMedGoogle Scholar
  32. 32.
    Mittendorfer B. Origins of metabolic complications in obesity: adipose tissue and free fatty acid trafficking. Curr Opin Clin Nutr Metab Care. 2011;14:535–41.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Zlobine I, Gopal K, Ussher JR. Lipotoxicity in obesity and diabetes-related cardiac dysfunction. Biochim Biophys Acta. 2016;1861:1555–68.CrossRefPubMedGoogle Scholar
  34. 34.
    Budui SL, Rossi AP, Zamboni M. The pathogenetic bases of sarcopenia. Clin Cases Miner Bone Metab. 2015;12:22–6.PubMedPubMedCentralGoogle Scholar
  35. 35.
    •• Ilich JZ, Kelly OJ, Inglis JE, Panton LB, Duque G, Ormsbee MJ. Interrelationship among muscle, fat, and bone: connecting the dots on cellular, hormonal, and whole body levels. Ageing Res Rev. 2014;15:51–60. Excellent review on the interrelationship between bone, muscle, and fat. CrossRefPubMedGoogle Scholar
  36. 36.
    Li J, Liu X, Zuo B, Zhang L. The role of bone marrow microenvironment in governing the balance between osteoblastogenesis and adipogenesis. Aging Dis. 2016;7:514–25.CrossRefPubMedGoogle Scholar
  37. 37.
    Ueda Y, Inaba M, Takada K, Fukui J, Sakaguchi Y, Tsuda M, et al. Induction of senile osteoporosis in normal mice by intra-bone marrow-bone marrow transplantation from osteoporosis-prone mice. Stem Cell. 2007;25:1356–63.CrossRefGoogle Scholar
  38. 38.
    Takada K, Inaba M, Ichioka N, Ueda Y, Taira M, Baba S, et al. Treatment of senile osteoporosis in SAMP6 mice by intra-bone marrow injection of allogeneic bone marrow cells. Stem Cells. 2006;24:399–405.CrossRefPubMedGoogle Scholar
  39. 39.
    Ichioka N, Inaba M, Kushida T, Esumi T, Takahara K, Inaba K, et al. Prevention of senile osteoporosis in SAMP6 mice by intrabone marrow injection of allogeneic bone marrow cells. Stem Cells. 2002;20:542–51.CrossRefPubMedGoogle Scholar
  40. 40.
    Verma S, Rajaratnam JH, Denton J, Hoyland JA, Byers RJ. Adipocytic proportion of bone marrow is inversely related to bone formation in osteoporosis. J Clin Pathol. 2002;55:693–8.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Cohen A, Dempster DW, Stein EM, Nickolas TL, Zhou H, McMahon DJ, et al. Increased marrow adiposity in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. 2012;97:2782–91.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gasparrini M, Rivas D, Elbaz A, Duque G. Differential expression of cytokines in subcutaneous and marrow fat of aging C57BL/6J mice. Exp Gerontol. 2009;44:613–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Casado-Díaz A, Santiago-Mora R, Dorado G, Quesada-Gómez JM. The omega-6 arachidonic fatty acid, but not the omega-3 fatty acids, inhibits osteoblastogenesis and induces adipogenesis of human mesenchymal stem cells: potential implication in osteoporosis. Osteoporos Int. 2013;24:1647–61.CrossRefPubMedGoogle Scholar
  44. 44.
    Kruger MC, Coetzee M, Haag M, Weiler H. Long-chain polyunsaturated fatty acids: selected mechanisms of action on bone. Prog Lipid Res. 2010;49:438–49.CrossRefPubMedGoogle Scholar
  45. 45.
    Elbaz A, Wu X, Gimble JM, Duque G. Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro. J Cell Mol Med. 2010;14:982–91.CrossRefPubMedGoogle Scholar
  46. 46.
    Griffith JF, Yeung DK, Ahuja AT, et al. A study of bone marrow and subcutaneous fatty acid composition in subjects of varying bone mineral density. Bone. 2009;44(6):1092–6.CrossRefPubMedGoogle Scholar
  47. 47.
    • Gunaratnam K, Vidal C, Gimble JM, Duque G. Mechanisms of palmitate-induced lipotoxicity in human osteoblasts. Endocrinology. 2014;155:108–16. First report on the mechanisms of lipotoxicity in osteoblasts in vitro. CrossRefPubMedGoogle Scholar
  48. 48.
    Gunaratnam K, Vidal C, Boadle R, Thekkedam C, Duque G. Mechanisms of palmitate-induced cell death in human osteoblasts. Biol Open. 2013;2:1382–9.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Greaves J, Chamberlain LH. DHHC palmitoyl transferases: substrate interactions and (patho)physiology. Trends Biochem Sci. 2011;36:245–53.CrossRefPubMedGoogle Scholar
  50. 50.
    Yeh L-CC, Ford JJ, Lee JC, Adamo ML. Palmitate attenuates osteoblast differentiation of fetal rat calvarial cells. Biochem Biophys Res Commun. 2014;450:777–81.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    • Takeshita S, Fumoto T, Naoe Y, Ikeda K. Age-related marrow adipogenesis is linked to increased expression of RANKL. J Biol Chem. 2014;289:16699–710. This paper reports the connection between marrow adipogenesis and increased bone resorption. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Drosatos-Tampakaki Z, Drosatos K, Siegelin Y, Gong S, Khan S, van Dyke T, et al. Palmitic acid and DGAT1 deficiency enhance osteoclastogenesis, while oleic acid-induced triglyceride formation prevents it. J Bone Miner Res. 2014;29:1183–95.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Mattiucci D, Maurizi G, Izzi V, Cenci L, Ciarlantini M, Mancini S, et al. Bone marrow adipocytes support hematopoietic stem cell survival. J Cell Physiol. 2018;233(2):1500–11.CrossRefPubMedGoogle Scholar
  54. 54.
    Bilwani FA, Knight KL. Adipocyte-derived soluble factor(s) inhibits early stages of B lymphopoiesis. J Immunology. 2012;189:4379–86.CrossRefGoogle Scholar
  55. 55.
    Weinstein RS, Manolagas SC. Apoptosis and osteoporosis. Am J Med. 2000;108:153–64.CrossRefPubMedGoogle Scholar
  56. 56.
    Mollazadeh S, Fazly Bazzaz BS, Kerachian MA. Role of apoptosis in pathogenesis and treatment of bone-related diseases. J Orthop Surg Res. 2015;10:15.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Unger RH, Orci L. Lipoapoptosis: its mechanism and its diseases. Biochim Biophys Acta. 2002;1585:202–12.CrossRefPubMedGoogle Scholar
  58. 58.
    Seeßle J, Liebisch G, Schmitz G, Stremmel W, Chamulitrat W. Palmitate activation by fatty acid transport protein 4 as a model system for hepatocellular apoptosis and steatosis. Biochim Biophys Acta. 2015;1851:549–65.CrossRefPubMedGoogle Scholar
  59. 59.
    Kim JE, Ahn MW, Baek SH, Lee IK, Kim YW, Kim JY, et al. AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast. Bone. 2008;43:394–404.CrossRefPubMedGoogle Scholar
  60. 60.
    Dong X, Bi L, He S, Meng G, Wei B, Jia S, et al. FFAs-ROS-ERK/P38 pathway plays a key role in adipocyte lipotoxicity on osteoblasts in co-culture. Biochimie. 2014;101:123–31.CrossRefPubMedGoogle Scholar
  61. 61.
    Veldhuis-Vlug AG, Rosen CJ. Mechanisms of marrow adiposity and its implications for skeletal health. Metabolism. 2017;67:106–14.CrossRefPubMedGoogle Scholar
  62. 62.
    Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metab. 2010;21:369–74.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol. 2015;16:461–72.CrossRefPubMedGoogle Scholar
  64. 64.
    Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284:12297–305.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Hosokawa N, Sasaki T, Lemura S, Natsume T, Hara T, Mizushima N. Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy. 2009;5:973–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK–Atg13–FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20:1992–2003.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Polson HE, de Lartigue J, Rigden DJ, Reedijk M, Urbe S, Clague MJ, et al. Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy. 2010;6:506–22.CrossRefPubMedGoogle Scholar
  68. 68.
    Hou J, Han ZP, Jing YY, Yang X, Zhang SS, Sun K, et al. Autophagy prevents irradiation injury and maintains stemness through decreasing ROS generation in mesenchymal stem cells. Cell Death Dis. 2013;4:e844.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Song C, Song C, Tong F. Autophagy induction is a survival response against oxidative stress in bone marrow-derived mesenchymal stromal cells. Cytotherapy. 2014;16:1361–70.CrossRefPubMedGoogle Scholar
  70. 70.
    Nuschke A, Rodrigues M, Stolz DB, Chu CT, Griffith L, Wells A. Human mesenchymal stem cells/multipotent stromal cells consume accumulated autophagosomes early in differentiation. Stem Cell Res Ther. 2014;5:140.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Nollet M, Santucci-Darmanin S, Breuil V, Al-Sahlanee R, Cros C, Topi M, et al. Autophagy in osteoblasts is involved in mineralization and bone homeostasis. Autophagy. 2014;10:1965–77.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Pantovic A, Krstic A, Janjetovic K, Kocic J, Harhaji-Trajkovic L, Bugarski D, et al. Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. Bone. 2013;52:524–31.CrossRefPubMedGoogle Scholar
  73. 73.
    Liu F, Fang F, Yuan H, Yang D, Chen Y, Williams L, et al. Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J Bone Miner Res. 2014;28:2414–30.CrossRefGoogle Scholar
  74. 74.
    Rohde M, Mayer H. Exocytotic process as a novel model for mineralization by osteoblasts in vitro and in vivo determined by electron microscopic analysis. Calcif Tissue Int. 2007;80:323–36.CrossRefPubMedGoogle Scholar
  75. 75.
    Boonrungsiman S, Gentleman E, Carzaniga R, Evans ND, McComb DW, Porter AE, et al. The role of intracellular calcium phosphate in osteoblast-mediated bone apatite formation. Proc Natl Acad Sci U S A. 2012;109:14170–5.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Mahamid J, Sharir A, Gur D, Zelzer E, Addadi L, Weiner S. Bone mineralization proceeds through intracellular calcium phosphate loaded vesicles: a cryo-electron microscopy study. J Struct Biol. 2011;174:527–35.CrossRefPubMedGoogle Scholar
  77. 77.
    Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci. 2010;13:805–11.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    • Hocking LJ, Whitehouse C, Helfrich MH. Autophagy: a new player in skeletal maintenance? J Bone Miner Res. 2012;27:1439–47. A good review on the role of autophagy in bone metabolism. CrossRefPubMedGoogle Scholar
  79. 79.
    Jilka RL, O'Brien CA. The role of osteocytes in age-related bone loss. Curr Osteoporos Rep. 2016;14:16–25.CrossRefPubMedGoogle Scholar
  80. 80.
    Zahm AM, Bohensky J, Adams CS, Shapiro IM, Srinivas V. Bone cell autophagy is regulated by environmental factors. Cell Tissues Organs. 2011;194:274–8.CrossRefGoogle Scholar
  81. 81.
    Yang Y, Zheng X, Li B, Jiang S, Jiang L. Increased activity of osteocyte autophagy in ovariectomized rats and its correlation with oxidative stress status and bone loss. Biochem Biophys Res Commun. 2014;451:86–92.CrossRefPubMedGoogle Scholar
  82. 82.
    Zhong X, Xiu L, Wei G, Pan T, Liu Y, Su L, et al. Bezafibrate prevents palmitate-induced apoptosis in osteoblastic MC3T3-E1 cells through the NF-κB signaling pathway. Int J Mol Med. 2011;28:535–42.PubMedGoogle Scholar
  83. 83.
    Gillet C, Spruyt D, Rigutto S, Dalla Valle A, Berlier J, Louis C, et al. Oleate abrogates palmitate-induced lipotoxicity and proinflammatory response in human bone marrow-derived mesenchymal stem cells and osteoblastic cells. Endocrinology. 2015;156:4081–93.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Lakshman Singh
    • 1
    • 2
  • Sonia Tyagi
    • 1
    • 2
  • Damian Myers
    • 1
    • 2
  • Gustavo Duque
    • 1
    • 2
  1. 1.Australian Institute for Musculoskeletal Science (AIMSS)The University of Melbourne and Western HealthSt. AlbansAustralia
  2. 2.Department of Medicine-Western Health, Melbourne Medical SchoolThe University of MelbourneSt. AlbansAustralia

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