Current Osteoporosis Reports

, Volume 16, Issue 2, pp 123–129 | Cite as

Marrow Fat—a New Target to Treat Bone Diseases?

  • Beata Lecka-Czernik
  • Sudipta Baroi
  • Lance A. Stechschulte
  • Amit Sopan Chougule
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


Purpose of Review

The goal of this review is to summarize recent findings on marrow adipose tissue (MAT) function and to discuss the possibility of targeting MAT for therapeutic purposes.

Recent Findings

MAT is characterized with high heterogeneity which may suggest both that marrow adipocytes originate from multiple different progenitors and/or their phenotype is determined by skeletal location and environmental cues. Close relationship to osteoblasts and heterogeneity suggests that MAT consists of cells representing spectrum of phenotypes ranging from lipid-filled adipocytes to pre-osteoblasts. We propose a term of adiposteoblast for describing phenotypic spectrum of MAT. Manipulating with MAT activity in diseases where impairment in energy metabolism correlates with bone functional deficit, such as aging and diabetes, may be beneficial for both. Paracrine activities of MAT might be considered for treatment of bone diseases.


MAT has unrecognized potential, either beneficial or detrimental, to regulate bone homeostasis in physiological and pathological conditions. More research is required to harness this potential for therapeutic purposes.


Marrow adipocytes Osteoporosis Beige fat Gene markers Energy metabolism 


Compliance with Ethical Standards

Conflict of Interest

Beata Lecka-Czernik, Sudipta Baroi, Lance Stechschulte, and Amit Sopan Chougule declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects.


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

  1. 1.
    Tavassoli M. Marrow adipose cells and hemopoiesis: an interpretative review. Exp Hematol. 1984;12(2):139–46.PubMedGoogle Scholar
  2. 2.
    Rappaport H, Raum M, Horrell JB. Bone marrow embolism. Am J Pathol. 1951;27(3):407–33.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Beresford JN, Bennett JH, Devlin C, Leboy PS, Owen ME. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J Cell Sci. 1992;102(Pt 2):341–51.PubMedGoogle Scholar
  4. 4.
    Horowitz MC, Berry R, Holtrup B, Sebo Z, Nelson T, Fretz JA, et al. Bone marrow adipocytes. Adipocyte. 2017;6:1–12. Scholar
  5. 5.
    Calo E, Quintero-Estades JA, Danielian PS, Nedelcu S, Berman SD, Lees JA. Rb regulates fate choice and lineage commitment in vivo. Nature. 2010;466(7310):1110–4.CrossRefPubMedPubMedCentralGoogle 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(6):771–84 e6. Scholar
  7. 7.
    Berry R, Rodeheffer MS, Rosen CJ, Horowitz MC. Adipose tissue residing progenitors (adipocyte lineage progenitors and adipose derived stem cells (ADSC)). Curr Mol Biol Rep. 2015;1(3):101–9. Scholar
  8. 8.
    Yue R, Zhou BO, Shimada IS, Zhao Z, Morrison SJ. Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell. 2016;18(6):782–96. Scholar
  9. 9.
    Zhou BO, Yu H, Yue R, Zhao Z, Rios JJ, Naveiras O, et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol. 2017;19(8):891–903. Scholar
  10. 10.
    Fan Y, Hanai JI, Le PT, Bi R, Maridas D, DeMambro V, et al. Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metab. 2017;25(3):661–72. Scholar
  11. 11.
    Worthley DL, Churchill M, Compton JT, Tailor Y, Rao M, Si Y, et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell. 2015;160(1–2):269–84. Scholar
  12. 12.
    • Lecka-Czernik B, Stechschulte LA, Czernik PJ, Sherman SB, Huang S, Krings A. Marrow adipose tissue: skeletal location, sexual dimorphism, and response to sex steroid deficiency. Front Endocrinol (Lausanne). 2017;8:188. This study suggests metabolic diversity among MAT in different skeletal locations and correlation with bone mass and sex steroids status. CrossRefPubMedCentralGoogle Scholar
  13. 13.
    •• 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. These studies represent the first indication of diverse phenotype of MAT. CrossRefPubMedPubMedCentralGoogle 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(2):546–52.CrossRefPubMedGoogle Scholar
  15. 15.
    Elbaz A, Rivas D, Duque G. Effect of estrogens on bone marrow adipogenesis and Sirt1 in aging C57BL/6J mice. Biogerontology. 2009;10(6):747–55. Scholar
  16. 16.
    Syed FA, Oursler MJ, Hefferanm TE, Peterson JM, Riggs BL, Khosla S. Effects of estrogen therapy on bone marrow adipocytes in postmenopausal osteoporotic women. Osteoporos Int. 2008;19(9):1323–30.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lecka-Czernik B, Stechschulte LA. Bone and fat: a relationship of different shades. Arch Biochem Biophys. 2014;561:124–9. Scholar
  18. 18.
    Lecka-Czernik B, Rosen CJ. Energy excess, glucose utilization, and skeletal remodeling: new insights. J Bone Miner Res. 2015;30(8):1356–61. Scholar
  19. 19.
    Elbaz A, Wu X, Rivas D, Gimble JM, Duque G. Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro. J Cell Mol Med. 2010;14(4):982–91. Scholar
  20. 20.
    • 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(8):2687–701. These studies identify for the first time bone anabolic secretome of beige-like MAT. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kolli V, Stechschulte LA, Dowling AR, Rahman S, Czernik PJ, Lecka-Czernik B. Partial agonist, telmisartan, maintains PPARgamma serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass. PLoS One. 2014;9(5):e96323. Scholar
  22. 22.
    • Stechschulte LA, Czernik PJ, Rotter ZC, Tausif FN, Corzo CA, Marciano DP, et al. PPARG post-translational modifications regulate bone formation and bone resorption. EBioMedicine. 2016;10:174–84. These studies demonstrated that SR10171 compound which acts as PPARγ inverse agonist has beneficial effect on bone and insulin sensitivity. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    • Stechschulte LA, Ge C, Hinds TD Jr, Sanchez ER, Franceschi RT, Lecka-Czernik B. Protein phosphatase PP5 controls bone mass and the negative effects of rosiglitazone on bone through reciprocal regulation of PPARgamma (peroxisome proliferator-activated receptor gamma) and RUNX2 (runt-related transcription factor 2). J Biol Chem. 2016;291(47):24475–86. These studies identify PP5 for its inhibitory effect on RUNX2 activity and anabolic activity of beige-like MAT. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell. 2001;106(5):563–73.CrossRefPubMedGoogle Scholar
  25. 25.
    Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology. 2007;148(6):2669–80.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Marciano DP, Kuruvilla DS, Boregowda SV, Asteian A, Hughes TS, Garcia-Ordonez R, et al. Pharmacological repression of PPARgamma promotes osteogenesis. Nat Commun. 2015;6:7443. Scholar
  27. 27.
    Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, et al. Rosiglitazone-associated fractures in type 2 diabetes: an analysis from a diabetes outcome progression trial (ADOPT). Diabetes Care. 2008;31(5):845–51.CrossRefPubMedGoogle Scholar
  28. 28.
    Modder UI, Monroe DG, Fraser DG, Spelsberg TC, Rosen CJ, Gehin M, et al. Skeletal consequences of deletion of steroid receptor coactivator-2/transcription intermediary factor-2. J Biol Chem. 2009;284(28):18767–77.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yang Y, Luo X, Xie X, Yan F, Chen G, Zhao W, et al. Influences of teriparatide administration on marrow fat content in postmenopausal osteopenic women using MR spectroscopy. Climacteric. 2016;19(3):285–91. Scholar
  30. 30.
    Kong J, Li YC. Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. Am J Physiol Endocrinol Metab. 2006;290(5):E916–24. Scholar
  31. 31.
    Lee H, Bae S, Yoon Y. Anti-adipogenic effects of 1,25-dihydroxyvitamin D3 are mediated by the maintenance of the wingless-type MMTV integration site/beta-catenin pathway. Int J Mol Med. 2012;30(5):1219–24. Scholar
  32. 32.
    Kelly KA, Gimble JM. 1,25-Dihydroxy vitamin D3 inhibits adipocyte differentiation and gene expression in murine bone marrow stromal cell clones and primary cultures. Endocrinology. 1998;139(5):2622–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Narvaez CJ, Simmons KM, Brunton J, Salinero A, Chittur SV, Welsh JE. Induction of STEAP4 correlates with 1,25-dihydroxyvitamin D3 stimulation of adipogenesis in mesenchymal progenitor cells derived from human adipose tissue. J Cell Physiol. 2013;228(10):2024–36. Scholar
  34. 34.
    Pathak K, Soares MJ, Calton EK, Zhao Y, Hallett J. Vitamin D supplementation and body weight status: a systematic review and meta-analysis of randomized controlled trials. Obes Rev. 2014;15(6):528–37. Scholar
  35. 35.
    Wright HM, Clish CB, Mikami T, Hauser S, Yanagi K, Hiramatsu R, et al. A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem. 2000;275(3):1873–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Santiago-Mora R, Casado-Diaz A, De Castro MD, Quesada-Gomez JM. Oleuropein enhances osteoblastogenesis and inhibits adipogenesis: the effect on differentiation in stem cells derived from bone marrow. Osteoporos Int. 2011;22(2):675–84. Scholar
  37. 37.
    Duque G, Li W, Vidal C, Bermeo S, Rivas D, Henderson J. Pharmacological inhibition of PPARgamma increases osteoblastogenesis and bone mass in male C57BL/6 mice. J Bone Miner Res. 2013;28(3):639–48. Scholar
  38. 38.
    Lecka-Czernik B, Rosen CJ. Skeletal integration of energy homeostasis: translational implications. Bone. 2016;82:35–41. Scholar
  39. 39.
    Liu JM, Rosen CJ, Ducy P, Kousteni S, Karsenty G. Regulation of glucose handling by the skeleton: insights from mouse and human studies. Diabetes. 2016;65(11):3225–32. Scholar
  40. 40.
    Mosialou I, Shikhel S, Liu JM, Maurizi A, Luo N, He Z, et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature. 2017;543(7645):385–90. Scholar
  41. 41.
    Scheller EL, Burr AA, MacDougald OA, Cawthorn WP. Inside out: bone marrow adipose tissue as a source of circulating adiponectin. Adipocyte. 2016;5(3):251–69. Scholar
  42. 42.
    Lecka-Czernik B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia. 2017;60:1163–9. Scholar
  43. 43.
    Chen MX, McPartlin AE, Brown L, Chen YH, Barker HM, Cohen PTA. Novel human protein serine/threonine phosphatase, which possesses four tetratricopeptide repeat motifs and localizes to the nucleus. EMBO J. 1994;13(18):4278–90.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Kang H, Sayner SL, Gross KL, Russell LC, Chinkers M. Identification of amino acids in the tetratricopeptide repeat and C-terminal domains of protein phosphatase 5 involved in autoinhibition and lipid activation. Biochemistry. 2001;40(35):10485–90.CrossRefPubMedGoogle Scholar
  45. 45.
    Hinds TD Jr, Sanchez ER. Protein phosphatase 5. Int J Biochem Cell Biol. 2008;40(11):2358–62. Scholar
  46. 46.
    Skinner J, Sinclair C, Romeo C, Armstrong D, Charbonneau H, Rossie S. Purification of a fatty acid-stimulated protein-serine/threonine phosphatase from bovine brain and its identification as a homolog of protein phosphatase 5. J Biol Chem. 1997;272(36):22464–71.CrossRefPubMedGoogle Scholar
  47. 47.
    Hinds TD Jr, Stechschulte LA, Cash HA, Whisler D, Banerjee A, Yong W, et al. Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid and PPAR{gamma} receptors. J Biol Chem. 2011;286(10):42911–22.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Cher C, Tremblay MH, Barber JR, Chung Ng S, Zhang B. Identification of chaulmoogric acid as a small molecule activator of protein phosphatase 5. Appl Biochem Biotechnol. 2010;160(5):1450–9. Scholar
  49. 49.
    Ramsey AJ, Chinkers M. Identification of potential physiological activators of protein phosphatase 5. Biochemistry. 2002;41(17):5625–32.CrossRefPubMedGoogle Scholar
  50. 50.
    Haslbeck V, Drazic A, Eckl JM, Alte F, Helmuth M, Popowicz G, Schmidt W, Braun F, Weiwad M, Fischer G, Gemmecker G, Sattler M, Striggow F, Groll M, Richter K Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism. Biosci Rep. 2015;35(3), e00210.
  51. 51.
    Hong TJ, Park K, Choi EW, Hahn JS. Ro 90-7501 inhibits PP5 through a novel, TPR-dependent mechanism. Biochem Biophys Res Commun. 2017;482(2):215–20. Scholar

Copyright information

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

Authors and Affiliations

  • Beata Lecka-Czernik
    • 1
  • Sudipta Baroi
    • 1
  • Lance A. Stechschulte
    • 1
  • Amit Sopan Chougule
    • 1
  1. 1.Department of Orthopaedic Research, Physiology and Pharmacology, Center for Diabetes and Endocrine ResearchUniversity of Toledo Health Sciences CampusToledoUSA

Personalised recommendations