Molecular Interaction of BMAT with Bone
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Purpose of Review
Bone marrow adipose tissue (BMAT) is a distinct adipose tissue with diverse local and systemic effects, affecting both physiological processes and pathological conditions, including hematopoiesis, bone remodeling, osteoporosis, obesity, anorexia nervosa, diabetes, and cancer. BMAT increases with age and bone loss, while the significance of this phenomenon has been neglected until recently. Bone cells and BMAT are mutually connected in terms of bone remodeling and energy metabolism. It has been suggested that high BMAT is caused by a shift in bone marrow mesenchymal stromal cell (BMSC) differentiation in favor of adipogenesis, and BMAT promotes bone loss through direct or indirect interaction with bone cells. However, it remains unclear why osteoporosis accelerates BMAT accumulation and what is the role of BMAT in bone remodeling and particularly in bone loss. The purpose of this review is to present the latest published data on the role of BMAT in physiological bone processes and during osteoporosis progression.
BMAT secretes numerous endocrine factors designated as adipokines as well as pro-inflammatory cytokines, which affect bone homeostasis through the regulation of osteoblast and osteoclast function. Most clinical data from osteoporotic patients demonstrate a negative relationship between BMAT and bone mass. Through technological advances in BMAT imaging, investigators are now able to quantify BMAT in humans and animal models. Pharmaceutical interventions targeting either bone loss or BMA expansion shed light in the understanding of the possible interactions between BMAT and bone cells.
A neglected feature of osteoporosis progression is BMAT development. BMAT appears as a “new tissue” with unique properties, which undoubtedly plays important physiological and pathological roles, but which remains insufficiently understood.
KeywordsOsteoporosis Bone marrow adipose tissue Bone remodeling Animal models Molecular mechanisms
Compliance with Ethical Standards
Conflict of Interest
Vagelis Rinotas and Eleni Douni declare no conflicts 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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 7.Ecklund K, Vajapeyam S, Feldman HA, Buzney CD, Mulkern RV, Kleinman PK, et al. Bone marrow changes in adolescent girls with anorexia nervosa. J Bone Miner Res. 2010;25(2):298–304. https://doi.org/10.1359/jbmr.090805.
- 8.Blebea JS, Houseni M, Torigian DA, Fan C, Mavi A, Zhuge Y, et al. Structural and functional imaging of normal bone marrow and evaluation of its age-related changes. Semin Nucl Med. 2007;37(3):185–94. https://doi.org/10.1053/j.semnuclmed.2007.01.002.
- 10.•• 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;6:1–13. https://doi.org/10.1038/ncomms8808. A study that provides a thorough characterization of regulated and constitutive marrow adipocyte tissues.
- 13.Li G, Xu Z, Fan J, Yuan W, Zhang L, Hou L, et al. To assess differential features of marrow adiposity between postmenopausal women with osteoarthritis and osteoporosis using water/fat MRI. Menopause. 2017;24(1):105–11. https://doi.org/10.1097/GME.0000000000000732.
- 14.Baum T, Yap SP, Dieckmeyer M, Ruschke S, Eggers H, Kooijman H, et al. Assessment of whole spine vertebral bone marrow fat using chemical shift-encoding based water-fat MRI. J Magn Reson Imaging. 2015;42(4):1018–23. https://doi.org/10.1002/jmri.24854.
- 15.Pansini V, Monnet A, Salleron J, Hardouin P, Cortet B, Cotten A. 3 Tesla 1H MR spectroscopy of hip bone marrow in a healthy population, assessment of normal fat content values and influence of age and sex. J Magn Reson Imaging. 2014;39(2):369–76. https://doi.org/10.1002/jmri.24176.CrossRefPubMedGoogle Scholar
- 17.Li X, Shet K, Xu K, Rodríguez JP, Pino AM, Kurhanewicz J, et al. Unsaturation level decreased in bone marrow fat of postmenopausal women with low bone density using high resolution magic angle spinning (HRMAS)1H NMR spectroscopy. Bone. 2017;105:87–92. https://doi.org/10.1016/j.bone.2017.08.014.
- 18.Arentsen L, Hansen KE, Yagi M, Takahashi Y, Shanley R, McArthur A, et al. Use of dual-energy computed tomography to measure skeletal-wide marrow composition and cancellous bone mineral density. J Bone Miner Metab. 2017;35(4):428–36. https://doi.org/10.1007/s00774-016-0796-1.
- 19.Patsch JM, Li X, Baum T, Yap SP, Karampinos DC, Schwartz AV, et al. Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures. J Bone Miner Res. 2013;28(8):1721–8. https://doi.org/10.1002/jbmr.1950.
- 20.•• Scheller EL, Troiano N, Vanhoutan JN, Bouxsein MA, Fretz JA, Xi Y, et al. Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo. Methods Enzymol. 2014;537:123–39. https://doi.org/10.1016/B978-0-12-411619-1.00007-0. This paper for the first time provides a new technical approach for the quantification of BMAT in rodents with osmium tetroxide and micro-CT. CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Gao Y, Zong K, Gao Z, Rubin MR, Chen J, Heymsfield SB, et al. Magnetic resonance imaging–measured bone marrow adipose tissue area is inversely related to cortical bone area in children and adolescents aged 5–18 years. JClin Densitom. 2015;18(2):203–8. https://doi.org/10.1016/j.jocd.2015.03.002.
- 24.Tang GY, Lv ZW, Tang RB, Liu Y, Peng YF, Li W, et al. Evaluation of MR spectroscopy and diffusion-weighted MRI in detecting bone marrow changes in postmenopausal women with osteoporosis. Clin Radiol. 2010;65(5):377–81. https://doi.org/10.1016/j.crad.2009.12.011.
- 25.Li GW, Xu Z, Chen QW, Tian YN, Wang XY, Zhou L, et al. Quantitative evaluation of vertebral marrow adipose tissue in postmenopausal female using MRI chemical shift-based water-fat separation. Clin Radiol. 2014;69(3):254–62. https://doi.org/10.1016/j.crad.2013.10.005.
- 27.Kugel H, Jung C, Schulte O, Heindel W. Age- and sex-specific differences in the 1H-spectrum of vertebral bone marrow. J Magn Reson Imaging. 2001;13:263–8. https://doi.org/10.1002/1522-2586(200102)13:2<263::AID-JMRI1038>3.0.CO;2-M.CrossRefPubMedGoogle Scholar
- 31.Bredella MA, Gerweck AV, Barber LA, Breggia A, Rosen CJ, Torriani M, et al. Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women. Bone. 2014;62:29–35. https://doi.org/10.1016/j.bone.2014.01.022.
- 32.•• Fan Y, Hanai J, Le PT BR, Maridas D, De Mambro V, et al. Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metab. 2017;25(3):661–72. https://doi.org/10.1016/j.cmet.2017.01.001. This paper shows that PTH regulates bone marrow mesenchymal stem cell fate between bone and adipocytes. CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Jin J, Wang L, Wang XK, Lai PL, Huang MJ, J D Di, et al. Risedronate inhibits bone marrow mesenchymal stem cell adipogenesis and switches RANKL/OPG ratio to impair osteoclast differentiation 2013;180(1):21–29. doi: https://doi.org/10.1016/j.jss.2012.03.018.
- 34.Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med. 1990;323(2):73–9. https://doi.org/10.1056/NEJM199007123230201.
- 35.Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 1995;333(22):1437–43. https://doi.org/10.1056/NEJM199511303332201.
- 36.Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85(11):4118–24. https://doi.org/10.1210/jcem.85.11.6953.
- 37.• Yang Y, Luo X, Yan F, Jiang Z, Li Y, Fang C, et al. Effect of zoledronic acid on vertebral marrow adiposity in postmenopausal osteoporosis assessed by MR spectroscopy. Skeletal Radiol. 2015;44(10):1499–505. https://doi.org/10.1007/s00256-015-2200-y. This study describes the beneficial anti-resorptive effects of zoledronic acid on vertebral marrow adiposity in postmenopausal osteoporosis.
- 39.Chandra A, Lin T, Young T, Tong W, Ma X, Tseng WJ, et al. Suppression of sclerostin alleviates radiation-induced bone loss by protecting bone-forming cells and their progenitors through distinct mechanisms. J Bone Miner Res. 2017;32(2):360–72. https://doi.org/10.1002/jbmr.2996.
- 42.• Sui B, Hu C, Liao L, Chen Y, Zhang X, Fu X, et al. Mesenchymal progenitors in osteopenias of diverse pathologies: differential characteristics in the common shift from osteoblastogenesis to adipogenesis. Sci Rep. 2016;6(1):30186. https://doi.org/10.1038/srep30186. This study gives a comparative analysis of the adipogenic and osteogenic potential of mesenchymal progenitors from various models of osteopenia. CrossRefPubMedPubMedCentralGoogle Scholar
- 43.•• Rinotas V, Niti A, Dacquin R, Bonnet N, Stolina M, Han C-Y, et al. Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice. J Bone Miner Res. 2014;29(5):1158–69. https://doi.org/10.1002/jbmr.2112. This paper describes two genetic mouse models of osteoporosis through the expression of human RANKL in transgenic mice, which develop an outstanding progressive BMAT phenotype.
- 44.Li G-W, Chang S-X, Fan J-Z, Tian Y-N, Xu Z, He Y-M. Marrow adiposity recovery after early zoledronic acid treatment of glucocorticoid-induced bone loss in rabbits assessed by magnetic resonance spectroscopy. Bone. 2013;52(2):668–75. https://doi.org/10.1016/j.bone.2012.11.002.CrossRefPubMedGoogle Scholar
- 45.Cao J, Ou G, Yang N, Ding K, Kream BE, Hamrick MW, et al. Impact of targeted PPARγ disruption on bone remodeling. Mol Cell Endocrinol. 2015;410:27–34. https://doi.org/10.1016/j.mce.2015.01.045.
- 47.Tabe Y, Yamamoto S, Saitoh K, Sekihara K, Monma N, Ikeo K, et al. Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells. Cancer Res. 2017;77(6):1453–64. https://doi.org/10.1158/0008-5472.CAN-16-1645.
- 48.Shafat MS, Oellerich T, Mohr S, Robinson SD, Edwards DR, Marlein CR, et al. Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Blood. 2017;129(10):1320–32. https://doi.org/10.1182/blood-2016-08-734798.
- 49.Sivasubramaniyan K, Lehnen D, Ghazanfari R, Sobiesiak M, Harichandan A, Mortha E, et al. Phenotypic and functional heterogeneity of human bone marrow- and amnion-derived MSC subsets. Ann N Y Acad Sci. 2012;1266(1):94–106. https://doi.org/10.1111/j.1749-6632.2012.06551.x.
- 54.Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, et al. PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 2008;22(21):2941–52. https://doi.org/10.1101/gad.1709008.
- 56.Kushwaha P, Khedgikar V, Gautam J, Dixit P, Chillara R, Verma A, et al. A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-β-catenin signaling. Cell Death Dis. 2014;5(9):e1422. https://doi.org/10.1038/cddis.2014.350.
- 58.Cho SW, Yang JY, Her SJ, Choi HJ, Jung JY, Sun HJ, et al. Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice. J Bone Miner Res. 2011;26(8):1939–52. https://doi.org/10.1002/jbmr.366.
- 60.Li M, Pan LC, Simmons HA, Li Y, Healy DR, Robinson BS, et al. Surface-specific effects of a PPARγ agonist, darglitazone, on bone in mice. Bone. 2006;39(4):796–806. https://doi.org/10.1016/j.bone.2006.04.008.
- 62.Kang Q, Song W-X, Luo Q, Tang N, Luo J, Luo X, et al. A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells Dev. 2009;18(4):545–58. https://doi.org/10.1089/scd.2008.0130.
- 64.Bennett CN, Ouyang H, Ma YL, Zeng Q, Gerin I, Sousa KM, et al. Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J Bone Miner Res. 2007;22(12):1924–32. https://doi.org/10.1359/jbmr.070810.
- 65.Stevens JR, Miranda-Carboni GA, Singer MA, Brugger SM, Lyons KM, Lane TF. Wnt10b deficiency results in age-dependent loss of bone mass and progressive reduction of mesenchymal progenitor cells. J Bone Miner Res. 2010;25(10):2138–47. https://doi.org/10.1002/jbmr.118.CrossRefPubMedPubMedCentralGoogle Scholar
- 66.Song BQ, Chi Y, Li X, Du WJ, Han ZB, Tian JJ, et al. Inhibition of notch signaling promotes the adipogenic differentiation of mesenchymal stem cells through autophagy activation and PTEN-PI3K/AKT/mTOR pathway. Cell Physiol Biochem. 2015;36(5):1991–2002. https://doi.org/10.1159/000430167.CrossRefPubMedGoogle Scholar
- 67.Shimizu T, Tanaka T, Iso T, Matsui H, Ooyama Y, Kawai-Kowase K, et al. Notch signaling pathway enhances bone morphogenetic protein 2 (BMP2) responsiveness of Msx2 gene to induce osteogenic differentiation and mineralization of vascular smooth muscle cells. J Biol Chem. 2011;286(21):19138–48. https://doi.org/10.1074/jbc.M110.175786.
- 69.James AW, Pang S, Askarinam A, Corselli M, Zara JN, Goyal R, et al. Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem Cells Dev. 2012;21(12):2170–8. https://doi.org/10.1089/scd.2011.0461.
- 71.Zhang L, Liu M, Zhou X, Liu Y, Jing B, Wang X, et al. Role of osteoprotegerin (OPG) in bone marrow adipogenesis. Cell Physiol Biochem. 2016;40:681–91. https://doi.org/10.1159/000452580.
- 75.Thommesen L, Stunes AK, Monjo M, Grøsvik K, Tamburstuen MV, Kjøbli E, et al. Expression and regulation of resistin in osteoblasts and osteoclasts indicate a role in bone metabolism. J Cell Biochem. 2006;99(3):824–34. https://doi.org/10.1002/jcb.20915.
- 76.Xie H, Tang SY, Luo XH, Huang J, Cui RR, Yuan LQ, et al. Insulin-like effects of visfatin on human osteoblasts. Calcif Tissue Int. 2007;80(3):201–10. https://doi.org/10.1007/s00223-006-0155-7.
- 77.Tu Q, Zhang J, Dong LQ, Saunders E, Luo E, Tang J, et al. Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1. J Biol Chem. 2011;286(14):12542–53. https://doi.org/10.1074/jbc.M110.152405.
- 83.Turner RT, Kalra SP, Wong CP, Philbrick KA, Lindenmaier LB, Boghossian S, et al. Peripheral leptin regulates bone formation. J Bone Miner Res. 2013;28(1):22–34. https://doi.org/10.1002/jbmr.1734.
- 86.Goto H, Hozumi A, Osaki M, Fukushima T, Sakamoto K, Yonekura A, et al. Primary human bone marrow adipocytes support TNF-α-induced osteoclast differentiation and function through RANKL expression. Cytokine. 2011;56(3):662–8. https://doi.org/10.1016/j.cyto.2011.09.005.
- 87.• Takeshita S, Fumoto T, Naoe Y, Ikeda K. Age-related marrow adipogenesis is linked to increased expression of RANKL. J Biol Chem. 2014;289(4):16699–710. https://doi.org/10.1074/jbc.M114.547919. This is the first study which describes the identification of a new subpopulation of pre-adipocytes that express RANKL and Pref1 which may have a role in bone loss during aging. CrossRefPubMedPubMedCentralGoogle Scholar
- 88.Wang Q-P, Li X-P, Wang M, Zhao L-L, Li H, Xie H, et al. Adiponectin exerts its negative effect on bone metabolism via OPG/RANKL pathway: an in vivo study. Endocrine. 2014;47(3):845–53. https://doi.org/10.1007/s12020-014-0216-z.
- 90.Luo X-H, Guo L-J, Xie H, Yuan L-Q, Wu X-P, Zhou H-D, et al. Adiponectin stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway. J Bone Miner Res. 2006;21(10):1648–56. https://doi.org/10.1359/jbmr.060707.