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Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 2/2018

01-04-2018 | Bone Marrow and Adipose Tissue (G Duque and B Lecka-Czernik, Section Editors)

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

Authors: Lakshman Singh, Sonia Tyagi, Damian Myers, Gustavo Duque

Published in: Current Osteoporosis Reports | Issue 2/2018

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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.
Literature
1.
Tamma R, Ribatti D. Bone niches, hematopoietic stem cells, and vessel formation. Int J Mol Sci. 2017;18(1):151.
2.
Craft CS, Scheller EL. Evolution of the marrow adipose tissue microenvironment. Calcif Tissue Int. 2017;100:461–75.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.
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.CrossRefPubMed
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. CrossRefPubMedPubMedCentral
7.
Kawai M, de Paula FJA, Rosen CJ. New insights into osteoporosis: the bone–fat connection. J Int Med. 2012;272:317–29.CrossRef
8.
9.
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.CrossRefPubMed
11.
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.CrossRefPubMed
13.
Ng A, Duque G. Osteoporosis as a lipotoxic disease. IBMS BoneKEy. 2010;7:108–23.CrossRef
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.CrossRefPubMed
15.
Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252–63.CrossRefPubMed
16.
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.CrossRefPubMed
18.
19.
20.
Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.CrossRefPubMed
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. PubMed
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.CrossRef
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
25.
Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone. 2012;50:534–9.CrossRefPubMed
26.
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. CrossRefPubMedPubMedCentral
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. CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
31.
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.CrossRefPubMedPubMedCentral
33.
Zlobine I, Gopal K, Ussher JR. Lipotoxicity in obesity and diabetes-related cardiac dysfunction. Biochim Biophys Acta. 2016;1861:1555–68.CrossRefPubMed
34.
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. CrossRefPubMed
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.CrossRefPubMed
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.CrossRef
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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. CrossRefPubMed
48.
49.
Greaves J, Chamberlain LH. DHHC palmitoyl transferases: substrate interactions and (patho)physiology. Trends Biochem Sci. 2011;36:245–53.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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. CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
54.
Bilwani FA, Knight KL. Adipocyte-derived soluble factor(s) inhibits early stages of B lymphopoiesis. J Immunology. 2012;189:4379–86.CrossRef
55.
56.
57.
Unger RH, Orci L. Lipoapoptosis: its mechanism and its diseases. Biochim Biophys Acta. 2002;1585:202–12.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
61.
Veldhuis-Vlug AG, Rosen CJ. Mechanisms of marrow adiposity and its implications for skeletal health. Metabolism. 2017;67:106–14.CrossRefPubMed
62.
63.
Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol. 2015;16:461–72.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRef
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
77.
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. CrossRefPubMed
79.
Jilka RL, O'Brien CA. The role of osteocytes in age-related bone loss. Curr Osteoporos Rep. 2016;14:16–25.CrossRefPubMed
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.CrossRef
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.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
Metadata
Title
Good, Bad, or Ugly: the Biological Roles of Bone Marrow Fat
Authors
Lakshman Singh
Sonia Tyagi
Damian Myers
Gustavo Duque
Publication date
01-04-2018
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 2/2018
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-018-0427-y

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