• 1
    Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611617.
  • 2
    Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 1994;79:11471156.
  • 3
    Tontonoz P, Spiegelman BM. Fat and beyond: The diverse biology of PPARγ. Ann Rev Biochem 2008;77:289312.
  • 4
    Betteridge DJ. Thiazolidinediones and fracture risk in patients with type 2 diabetes. Diab Med 2011;28:759771.
  • 5
    Meunier P, Aaron J, Edouard C, Vlgnon G. Osteoporosis and the replacement of cell populations of the marrow by adipose tissue: A quantitative study of 84 iliac bone biopsies. Clin Orthopaed Relat Res 1971;80:147154.
  • 6
    Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung U-i, Kubota N, Terauchi Y, Harada Y, Azuma Y, Nakamura K, Kadowaki T, Kawaguchi H. PPAR γ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 2004;113:846855.
  • 7
    Liu L-F, Shen W-J, Zhang ZH, Wang LJ, Kraemer FB. Adipocytes decrease Runx2 expression in osteoblastic cells: Roles of PPARγ and adiponectin. J Cell Physiol 2010;225:837845.
  • 8
    Shinoda Y, Yamaguchi M, Ogata N, Akune T, Kubota N, Yamauchi T, Terauchi Y, Kadowaki T, Takeuchi Y, Fukumoto S, Ikeda T, Hoshi K, Chung U-i, Nakamura K, Kawaguchi H. Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways. J Cell Biochem 2006;99:196208.
  • 9
    Scheller EL, Song J, Dishowitz MI, Soki FN, Hankenson KD, Krebsbach PH. Leptin functions peripherally to regulate differentiation of mesenchymal progenitor cells. Stem Cells 2010;28:10711080.
  • 10
    Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: A central control of bone mass. Cell 2000;100:197207.
  • 11
    Mbalaviele G, Abu-Amer Y, Meng A, Jaiswal R, Beck S, Pittenger MF, Thiede MA, Marshak DR. Activation of peroxisome proliferator-activated receptor-γ pathway inhibits osteoclast differentiation. J Biological Chem 2000;275:1438814393.
  • 12
    Maurin AC, Chavassieux PM, Meunier PJ. Expression of PPARγ and β/δ in human primary osteoblastic cells: Influence of polyunsaturated fatty acids. Calc Tissue Int 2005;76:385392.
  • 13
    Jackson SM, Demer LL. Peroxisome proliferator-activated receptor activators modulate the osteoblastic maturation of MC3T3-E1 preosteoblasts. FEBS Lett 2000;471:119124.
  • 14
    Cho SW, Yang J-Y, Her SJ, Choi HJ, Jung JY, Sun HJ, An JH, Cho HY, Kim SW, Park KS, Kim SY, Baek W-Y, Kim J-E, Yim M, Shin CS. Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice. J Bone Mineral Res 2011;26:19391952.
  • 15
    Kim SW, Her SJ, Kim SY, Shin CS. Ectopic overexpression of adipogenic transcription factors induces transdifferentiation of MC3T3-E1 osteoblasts. Biochem Biophys Res Commun 2005;327:811819.
  • 16
    Botolin S, McCabe LR. Inhibition of PPARγ prevents type I diabetic bone marrow adiposity but not bone loss. J Cell Physiol 2006;209:967976.
  • 17
    Yu W-H, Li F-G, Chen X-Y, Li J-T, Wu Y-H, Huang L-H, Wang Z, Li P, Wang T, Lahn BT, Xiang AP. PPARγ suppression inhibits adipogenesis but does not promote osteogenesis of human mesenchymal stem cells. Int J Biochem Cell Biol 2011;44:377384.
  • 18
    Zoncu R, Efeyan A, Sabatini DM. mTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011;12:2135.
  • 19
    Akiyama TE, Sakai S, Lambert G, Nicol CJ, Matsusue K, Pimprale S, Lee Y-H, Ricote M, Glass CK, Brewer HB, Gonzalez FJ. Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and Apoe in macrophages and reduced cholesterol efflux. Mol Cell Biol 2002;22:26072619.
  • 20
    Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K-i, Hara K, Tanaka N, Avruch J, Yonezawa K. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mtor substrates p70 S6 kinase and 4E-BP1 through their Tor signaling (Tos) motif. J Biological Chem 2003;278:1546115464.
  • 21
    Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6:11221128.
  • 22
    Sampath P, Pritchard DK, Pabon L, Reinecke H, Schwartz SM, Morris DR, Murry CE. A hierarchical network controls protein translation during murine embryonic stem cell self-renewal and differentiation. Cell Stem Cell 2008;2:448460.
  • 23
    Dunlop EA, Dodd KM, Seymour LA, Tee AR. Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein–protein interactions for substrate recognition. Cell Signal 2009;21:10731084.
  • 24
    Easley CAt, Ben-Yehudah A, Redinger CJ, Oliver SL, Varum ST, Eisinger VM, Carlisle DL, Donovan PJ, Schatten GP. mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell Reprogram 2010;12:26373.
  • 25
    Turnquist HR, Cardinal J, Macedo C, Rosborough BR, Sumpter TL, Geller DA, Metes D, Thomson AW. mTOR and GSK-3 shape the CD4+ T-cell stimulatory and differentiation capacity of myeloid DCs after exposure to LPS. Blood 2010;115:475869.
  • 26
    Kim J, Jung Y, Sun H, Joseph J, Mishra A, Shiozawa Y, Wang J, Krebsbach PH, Taichman RS. Erythropoietin mediated bone formation is regulated by mTOR signaling. J Cell Biochem 2012;113:220228.
  • 27
    Kim J-K, Baker J, Nor JE, Hill EE. mTor plays an important role in odontoblast differentiation. J Endodont 2011;37:10811085.
  • 28
    Tang C-H, Lu D-Y, Tan T-W, Fu W-M, Yang R-S. Ultrasound induces hypoxia-inducible factor-1 activation and inducible nitric-oxide synthase expression through the integrin/integrin-linked kinase/Akt/mammalian target of rapamycin pathway in osteoblasts. J Biological Chem 2007;282:2540625415.
  • 29
    Singha UK, Jiang Y, Yu S, Luo M, Lu Y, Zhang J, Xiao G. Rapamycin inhibits osteoblast proliferation and differentiation in MC3T3-E1 cells and primary mouse bone marrow stromal cells. J Cell Biochem 2008;103:434446.
  • 30
    Tseng W-P, Yang S-N, Lai C-H, Tang C-H. Hypoxia induces BMP-2 expression via ILK, Akt, mTOR, and HIF-1 pathways in osteoblasts. J Cell Physiol 2010;223:810818.
  • 31
    Xian L, Wu X, Pang L, Lou M, Rosen CJ, Qiu T, Crane J, Frassica F, Zhang L, Rodriguez JP, Jia X, Yakar S, Xuan S, Efstratiadis A, Wan M, Cao X. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med 2012;18:10951101.
  • 32
    Laplante M, Sabatini DM. An emerging role of Mtor in lipid biosynthesis. Curr Biol 2009;19:R1046R1052.
  • 33
    Kim JE, Chen J. Regulation of peroxisome proliferator–activated receptor-γ activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 2004;53:27482756.
  • 34
    Krebsbach PH, Kuznetsov SA, Satomura K, Emmons RVB, Rowe DW, Robey PG. Bone formation in vivo: Comparison of osteogenesis by transplanted mouse and human marrow stromal fibroblasts. Transplantation 1997;63:10591069.
  • 35
    Sun H, Dai K, Tang T, Zhang X. Regulation of osteoblast differentiation by Slit2 in osteoblastic cells. Cell Tissue Organ 2009;190:6980.
  • 36
    Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, MacDougald OA. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A 2005;102:33243329.
  • 37
    Nicol CJ, Yoon M, Ward JM, Yamashita M, Fukamachi K, Peters JM, Gonzalez FJ. PPARγ influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis. Carcinogenesis 2004;25:17471755.
  • 38
    Rodda SJ, McMahon AP. Distinct roles for hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 2006;133:32313244.
  • 39
    Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C. Life without white fat: A transgenic mouse. Genes Dev 1998;12:316881.
  • 40
    Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Mineral Res 2010;25:14681486.
  • 41
    Wan YH. PPAR gamma in bone homeostasis. Trends Endocrinol Metabol 2010;21:722728.
  • 42
    Lecka-Czernik B. PPAR[gamma], an essential regulator of bone mass: Metabolic and molecular cues. IBMS Bonekey 2010;7:171181.
  • 43
    Magri CJ, Gatt N, Xuereb RG, Fava S. Peroxisome proliferator-activated receptor-γ and the endothelium: Implications in cardiovascular disease. Expert Rev Cardiovasc Ther 2011;9:12791294.
  • 44
    Devlin MJ, Kawai M, Rosen CJ. Fat targets for skeletal health. Nature Rev Rheumatol 2009; 5:365.
  • 45
    Wan Y, Chong L-W, Evans RM. PPAR-[gamma] regulates osteoclastogenesis in mice. Nat Med 2007;13:14961503.
  • 46
    Gerber H-P, Ferrara N. Angiogenesis and bone growth. Trends Cardiovasc Med 2000;10:223228.
  • 47
    Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B. Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 2004;145:401406.
  • 48
    Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 2005;146:12261235.
  • 49
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143147.
  • 50
    Halade GV, El Jamali A, Williams PJ, Fajardo RJ, Fernandes G. Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice. Exp Gerontol 2011;46:4352.
  • 51
    Luo X-H, Guo L-J, Xie H, Yuan L-Q, Wu X-P, Zhou H-D, Liao E-Y. Adiponectin Stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway. J Bone Mineral Res 2006;21:16481656.
  • 52
    Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 2009:460:259263.
  • 53
    Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL. Divergent effects of selective peroxisome proliferator-activated receptor-γ2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 2002;143:23762384.
  • 54
    Shockley KR, Lazarenko OP, Czernik PJ, Rosen CJ, Churchill GA, Lecka-Czernik B. PPARγ2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem 2009;106:232246.
  • 55
    Frost HM. Tetracycline-based histological analysis of bone remodeling. Calcified Tissue Res 1969;3:211.
  • 56
    Branda CS, Dymecki SM. Talking about a revolution: The impact of site-specific recombinases on genetic analyses in mice developmental. Cell 2004;6:728.
  • 57
    Payne JB, Golub LM. Using tetracyclines to treat osteoporotic/osteopenic bone loss: From the basic science laboratory to the clinic. Pharmacological research. 2011;63:121129.