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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 劉興華(Shing-Hwa Liu) | |
dc.contributor.author | Chia-Chi Chuang | en |
dc.contributor.author | 莊佳琪 | zh_TW |
dc.date.accessioned | 2021-06-13T16:27:55Z | - |
dc.date.available | 2005-08-02 | |
dc.date.copyright | 2005-08-02 | |
dc.date.issued | 2005 | |
dc.date.submitted | 2005-07-14 | |
dc.identifier.citation | Ahmed N, Grmes HL, Bllacosa A, Chen TO, Tsichlis PN (1997) Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc Natl Acad Sci USA 94:3627-3632.
Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, Terauchi Y, Harada Y, Azuma Y, Nakamura K, Kadowaki T, Kawaguchi H (2004) PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 113:846-855. Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL (2005) Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 146:1226-1235. American Diabetes Association Home Page Aubin JE (1998) Bone stem cells. J Cell Biochem Suppl 30-31:73-82. Auwerx J, Dequeker J, Bouillon R, Geusens P, Nijs J (1988) Mineral metabolism and bone mass at peripheral and axial skeleton in diabetes mellitus. Diabetes 37:8-12. Barrett-Conner E, Holbrook T (1992) Sex differences in osteoporosis in older adults with non-insulin-dependent diabetes mellitus. JAMA 268:3333-3337. Bell-Parikh LC, Ide T, Lawson JA, McNamara P, Reilly M, FitzGerald GA (2003) Biosynthesis of 15-deoxy-delta12,14-PGJ2 and the ligation of PPARgamma. J Clin Invest 112:945-955. Botolin S, Faugere MC, Malluche H, Orth M, Meyer R, McCabe LR (2005) Increased bone adiposity and PPARγ2 expression in type I diabetic mice. Endocrinology May 19; [Epub ahead of print] Borgatti P, Martelli AM, Bellacosa A, Casto R, Massari L, Capitani S, Neri LM (2000) Translocation of Akt/PKB to the nucleus of osteoblast-like MC3T3-E1 cells exposed to proliferative growth factors. FEBS Lett 477:27-32. Bouillon R (1991) Diabetic bone disease [editorial]. Calcif Tissue Int 49:155-160. Bouillon R, Bex M, Van Herck E, Laureys J, Dooms L, Lesaffre E, Ravussin E (1995) Influence of age, sex, and insulin on osteoblast function: osteoblast dysfunction in diabetes mellitus. J Clin Endocrinol Metab 80:1194-1202. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337-342. Brook CG, Lloyd JK, Wolf OH (1972) Relation between age of onset of obesity and size and number of adipose cells. Br Med J 2:25-27. Buysschaert M, Cauwe F, Jamart J, Brichant C, De Coster P, Magnan A, Donckier J (1992) Proximal femur density in type 1 and 2 diabetic patients. Diabete Metab 18:32-37. Cao Z, Umek RM, McKnight SL (1991) Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev 5:1538-1552. Carpio L, Gladu J, Goltzman D, Rabbani SA (2001) Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. Am J Physiol Endocrinol Metab 281:E489-499. Chaudhary LR, Hruska KA (2001) The cell survival signal Akt is differentially activated by PDGF-BB, EGF, and FGF-2 in osteoblastic cells. J Cell Biochem 81:304-311. Clark JM, Brancati FL, Diehl AM (2002) Nonalcoholic fatty liver disease. Gastroenterology 122:1649-1657. Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS, Hunt CR, Spiegelman BM (1987) Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237:402-405. Danciu TE, Adam RM, Naruse K, Freeman MR, Hauschka PV (2003) Calcium regulates the PI3K-Akt pathway in stretched osteoblasts. FEBS Lett 536:193-197. Debiais F, Lasmoles F, Lefevre G, Mascarelli F, Marie PJ (2002) Glycogen synthase kinase-3 (GSK-3) signaling is involved in the anti-apoptotic effect of fibroblast growth factor-2 in human calvaria osteoblasts. ASBMR 24th Annual Meeting Abstract SA 138. Ducy P, Karsenty G (1995) Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene. Mol Cell Biol 15:1858-1869. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation. Cell 89:747-754. Entingh AJ, Taniguchi CM, Kahn CR (2003) Bi-directional regulation of brown fat adipogenesis by the insulin receptor. J Biol Chem 278:33377-33383. Fajas L (2003) Adipogenesis: a cross-talk between cell proliferation and cell differentiation. Ann Med 35:79-85. Farmer SR (2005) Regulation of PPARgamma activity during adipogenesis. Int J Obes Relat Metab Disord 29 Suppl 1:S13-16. Fasshauer M, Klein J, Kriauciunas KM, Ueki K, Benito M, Kahn CR (2001) Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes. Mol Cell Biol 21:319-329. Flier JS (1995) The adipocyte: storage depot or node on the energy information superhighway? Cell 80:15-18. Folk JW, Starr AJ, Early JS (1999) Early wound complications of operative treatment of calcaneus fractures: analysis of 190 fractures. J Orthop Trauma 13:369-372. Forsen L, Meyer HE, Midthjell K, Edna TH (1999) Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trondelag Health Survey. Diabetologia 42:920-925. Fruhbeck G, Gomez-Ambrosi J, Muruzabal FJ, Burrell MA (2001) The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280:E827-847. Gagnon A, Chen CS, Sorisky A (1999) Activation of protein kinase B and induction of adipogenesis by insulin in 3T3-L1 preadipocytes: contribution of phosphoinositide-3,4,5-trisphosphate versus phosphoinositide-3,4-bisphosphate. Diabetes 48:691–698 Gebauer G, Lin S, Beam H, Vieira P, Parsons J (2002) Low-intensity pulsed ultrasound increases the fracture callus strength in diabetic BB Wistar rats but does not affect cellular proliferation. J Orthop Res 20:587-592. Geoffroy V, Ducy P, Karsenty G (1995) A PEBP2 alpha/AML-1-related factor increases osteocalcin promoter activity through its binding to an osteoblast-specific cis-acting element. J Biol Chem 270:30973-30979. Ghosh-Choudhury N, Abboud SL, Nishimura R, Celeste A, Mahimainathan L, Choudhury GG (2002) Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription. J Biol Chem 277:33361-33368. Gimble JM, Morgan C, Kelly K, Wu X, Dandapani V, Wang CS, Rosen V (1995) Bone morphogenetic proteins inhibit adipocyte differentiation by bone marrow stromal cells J Cell Biochem 58:393-402. Gregoire FM, Smas CM, Sul HS (1998) Understanding adipocyte differentiation. Physiol Rev 78:783-809. Gunczler P, Lanes R, Paz-Martinez V, Martins R, Esaa S, Colmenares V, Weisinger JR (1998) Decreased lumbar spine bone mass and low bone turnover in children and adolescents with insulin dependent diabetes mellitus followed longitudinally. J Pediatr Endocrinol Metab 11:413-419. Hampson G, Evans C, Petitt RJ, Evans WD, Woodhead SJ, Peters JR, Ralston SH (1998) Bone mineral density, collagen type 1 alpha 1 genotypes and bone turnover in premenopausal women with diabetes mellitus. Diabetologia 41:1314-1320. Harada S, Rodan GA (2003) Control of osteoblast function and regulation of bone mass. Nature 423:349-355. Harmey D, Stenbeck G, Nobes CD, Lax AJ, Grigoriadis AE (2004) Regulation of Osteoblast Differentiation by Pasteurella Multocida Toxin (PMT): A Role for Rho GTPase in Bone Formation. J Bone Miner Res 19:661-668. Hausman DB, DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ (2001) The biology of white adipocyte proliferation. Obes Rev 2:239-254. Herold K, Vezys V, Sun Q, Viktora D, Seung E, Reiner S, Brown D (1996) Regulation of cytokine production during development of autoimmune diabetes induced with multiple low doses of streptozotocin. J Immunol 156:3521-3527. Herrero S, Calvo OM, Garcia-Moreno C, Martin E, San Roman JI, Martin M, Garcia-Talavera JR, Calvo JJ, del Pino-Montes J (1998) Low bone density with normal bone turnover in ovariectomized and streptozotocin-induced diabetic rats. Calcif Tissue Int 62:260-265. Herskind AM, Christensen K, Norgaard-Andersen K, Andersen JF (1992) Diabetes mellitus and healing of closed fractures. Diabete Metab 18:63-64 Herzog EL, Chai L, Krause DS (2003) Plasticity of marrow-derived stem cells. Blood 102:3483-3493. Horcajada-Molteni MN, Chanteranne B, Lebecque P, Davicco MJ, Coxam V, Young A, Barlet JP (2001) Amylin and bone metabolism in streptozotocin induced diabetic rats. J Bone Miner Res 16:958-965. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87-91. Hu E, Liang P, Spiegelman BM (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697-10703. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK (1999) Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 400:378-382. Huang JC, Sakata T, Pfleger LL, Bencsik M, Halloran BP, Bikle DD, Nissenson RA (2004) PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res 19:235-244. Hui SL, Epstein S, Johnston CC, Jr. (1985) A prospective study of bone mass in patients with type I diabetes. J Clin Endocrinol Metab 60:74-78 Jennermann C, Triantafillou J, Cowan D, Pennink BGA, Connolly KM, Morris DC (1995) Effects of thiazolidinediones on bone turnover in the rat. J Bone Miner Res 10:S241 (Abstract) Jeon MJ, Kim JA, Kwon SH, Kim SW, Park KS, Park SW, Kim SY, Shin CS (2003) Activation of Peroxisome Proliferator-activated Receptor-γ Inhibits the Runx2-mediated Transcription of Osteocalcin in Osteoblasts. J Biol Chem 278:23270-23277. Jilka RL, Weinstein RS, Takahashi K, Parfitt AM, Manolagas SC (1996) Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence. J Clin Invest 97:1732-1740. Johnston CJ, Hui S, Longcope C (1985) Bone mass and sex steroid concentrations in postmenopausal Caucasian diabetics. Metabolism 34:544-550. Kadiyala S, Young RG, Thiede MA, Bruder SP (1997) Culture expanded canine mesenchymal stem cells possess osteochondrogenic potential in vivo and in vitro. Cell Transplantation 6:125-134. Kahn CR, Chen L, Cohen SE (2000) Unraveling the mechanism of action of thiazolidinediones. J Clin Invest 106:1305-1307. Kajkenova O, Lecka-Czernik B, Gubrij I, Hauser SP, Takahashi K, Parfitt AM, Jilka RL, Manolagas SC, Lipschitz DA (1997) Increased adipogenesis and myelopoiesis in the bone marrow of SAMP6, a murine model of defective osteoblastogenesis and low turnover osteopenia. J Bone Miner Res 12:1772-1779. Kaliman P, Vinals F, Testar X, Palacin M, Zorzano A (1995) Disruption of Glut1 glucose carrier trafficing in L6E9 and Sol8 myoblasts by the phosphatidylinositol 3-kinase inhibitor wortmannin. Biochem J 312:471-477. Karsenty G, Wagner EF (2002) Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2:389-406. Kemink SA, Hermus AR, Swinkels LM, Lutterman JA, Smals AG (2000) Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. J Endocrinol Invest 23:295-303. Khan E, Abu-Amer Y (2003) Activation of peroxisome proliferator-activated receptor-gamma inhibits differentiation of preosteoblasts. J Lab Clin Med 142:29-34. Kimura K, Hattori S, Kabuyama Y, Shizawa Y, Takayanagi J, Nakamura S, Toki S, Matsuda Y, Onodera K, Fukui Y (1994) Neurite outgrowth of PC12 cells is suppressed by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. J Biol Chem 269:18961-18967. Knittle JL, Timmers K, Ginsberg-Fellner F (1979) The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. J Clin Invest 295:349-353. Kohn AD, Summers SA, Birnbaum MJ, Roth RA (1996) Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem 271:31372–31378. Krakauer J, McKenna M, Burderer N, Rao D, Whitehouse F, Parfitt A (1995) Bone loss and bone turnover in diabetes. Diabetes 44:775–782. Kunjathoor V, Wilson D, LeBoeuf R (1996) Increased atherosclerosis in streptozotocin-induced diabetic mice. J Clin Invest 97:1767–1773. Kuo ML, Chuang SE, Lin MT, Yang SY (2001) The involvement of PI3-K/Akt dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6. Oncogene 20:677-685. Lecka-Czernik B, Gubrij I, Moerman EJ, Kajkenova O, Lipschitz DA, Manolagas SC, Jilka RL (1999) Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2. J Cell Biochem 74:357–371. Levin M, Boisseau V, Avioli L (1976) Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes. N Engl J Med 294:241–245. Lin FT, Lane MD (1994) CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc Natl Acad Sci U S A 91:8757-8761. Lin MT, Lee RC, Yang PC, Ho FM, and Kuo ML (2001) Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells. Involvement of phosphatidylinositol 3-kinase/akt pathway. J Biol Chem 276: 48997-49002. Lukic M (1998) Effector mechanisms in low-dose streptozotocin-induced diabetes. Dev Immunol 6:119–128. Lundgren CH, Brown SL, Nordt TK, Sobel BE, Fujii S (1996) Elaboration of type-1 plasminogen activator inhibitor from adipocytes: A potential pathogenetic link between obesity and cardiovascular disease. Circulation 93:106-110. MacDougald OA, Mandrup S (2002) Adipogenesis: Forces that tip the scales. Trends Endocrinol Metab 13:5-11. Macey L, Kana SM, Jingushi S, Terek RM, Borretos J, Bolander ME (1989) Defects of early fracture-healing in experimental diabetes. J Bone Joint Surg Am 71:722-733. Magun R, Burgering BM, Coffer PJ, Pardasani D, Lin Y, Chabot J, Sorisky A (1996) Expression of a constitutively activated form of protein kinase B (c-AKT) in 3T3-L1 preadipose cells causes spontaneous differentiation. Endocrinology 137:3590-3593. Martin DR, Cox NR, Hathcock TL, Niemeyer GP, Baker HJ (2002) Isolation and characterization of multipotential mesenchymal stem cells from feline bone marrow. Exp Hematol 30:879-886. McCracken M, Lemons JE, Rahemtulla F, Prince CW, Feldman D (2000) Bone response to titanium alloy implants placed in diabetic rats. Int J Oral Maxillofac Implants 15:345-354. McKee MD, Glimcher MJ, Nanci A (1992) High-resolution immunolocalization of osteopontin and osteocalcin in bone and cartilage during endochondral ossification in the chicken tibia. Anat Rec 234:479-492. McNair P, Christiansen C, Christensen MS, Madsbad S, Faber OK, Binder C, Transbol I (1981) Development of bone mineral loss in insulin-treated diabetes: a 1 1/2 years follow-up study in sixty patients. Eur J Clin Invest 11:55-59. Meirelles Lda S, Nardi NB (2003) Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization. Brit J Haematol 123:702-711. Merriman HL, van Wijnen AJ, Hiebert S, Bidwell JP, Fey E, Lian J, Stein J, Stein GS (1995) The tissue-specific nuclear matrix protein, NMP-2, is a member of the AML/CBF/PEBP2/runt domain transcription factor family: interactions with the osteocalcin gene promoter. Biochemistry 34:13125-13132. Meyer HE, Tverdal A, Falch JA (1993) Risk factors for hip fracture in middleaged Norwegian women and men. Am J Epidemiol 137:1203-1211. Moerman EJ, Teng K, Lipschitz DA, Lecka-Czernik B (2004) Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGFbeta/BMP signaling pathways. Aging Cell 3:379-389. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP (2001) The continuing epidemics of obesity and diabetes in the United States. JAMA 286:1195-200. Mosca JD, Hendricks JK, Buyaner D, Davis-Sproul J, Chuang LC, Majumdar MK, Chopra R, Barry F, Murphy M, Thiede MA, Junker U, Rigg RJ, Forestell SP, Bo¨hnlein E, Storb R, Sandmaier BM (2000) Mesenchymal stem cells as vehicles for gene delivery. Clin Orthop Relat R 379S:S71-S90. Mosci P, Vecchiarelli A, Cenci E, Puliti Ma, Bistoni F (1993) Low-dose streptozotocin- induced diabetes in mice. Cell Immunol 150:27-35. Munoz-Torres M, Jodar E, Escobar-Jimenez F, Lopez-Ibarra PJ, Luna JD (1996) Bone mineral density measured by dual X-ray absorptiometry in Spanish patients with insulin-dependent diabetes mellitus. Calcif Tissue Int 58:316-319. Novakofski J (2004) Adipogenesis: Usefulness of in vitro and in vivo experimental models. J Anim Sci 82:905-915. Nuttall ME, Gimble JM (2004) Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications. Curr Opin Pharmacol 4:290-294. Owen TA, Aronow M, Shalhoub V, Barone LM, Wilming L, Tassinari MS, Kennedy MB, Pockwinse S, Lian JB, Stein GS (1990) Progressive development of the rat osteoblast phenotype in vitro: Reciprocal relationships in expression of genes associated with osteoblast proliferation and differentiation during formation of the bone extracellular matrix. J Cell Physiol 143:420-430. Pechhold K, Patterson NB, Blum C, Fleischacker CL, Boehm BO, Harlan DM (2001) Low dose streptozotocin-induced diabetes in rat insulin promotermCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent. J Immunol 166:2531-2539. Pei L, Tontonoz P (2004) Fat’s loss is bone’s gain. J Clin Invest 113:805-806. Pereira RF, Halford KW, O'Hara MD, Leeper DB, Sokolov BP, Pollard MD, Bagasra O, Prockop DJ (1995) Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci USA 92:4857-4861. Phinney DG, Kopen G, Isaacson RL, Prockop DJ (1999) Plastic Adherent Stromal Cells From the Bone Marrow of Commonly Used Strains of Inbred Mice: Variations in Yield, Growth, and Differentiation. J Cell Biochem 72:570-585. Phinney DG (2002) Building a consensus regarding the nature and origin of mesenchymal stem cells. J Cell Biochem 38(Suppl.):7-12. Piepkorn B, Kann P, Forst T, Andreas J, Pfutzner A, Beyer J (1997) Bone mineral density and bone metabolism in diabetes mellitus. Horm Metab Res 29:584-591. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143-147. Price PA, Otsuka AA, Poser JW, Kristaponis J, Raman N (1976) Characterization of a gamma-carboxyglutamic acid-containing protein from bone. Proc Natl Acad Sci USA 73:1447-1451. Rangwala SM, Lazar MA (2000) Transcriptional control of adipogenesis. Annu Rev Nutr 20:535-559. Ren D, Collingwood TN, Rebar EJ, Wolffe AP, Camp HS (2002) PPARγ knockdown by engineered transcription factors: exogenous PPARγ2 but not PPARγ1 reactivates adipogenesis. Genes Dev 16:27-32. Rosen ED, Spiegelman BM (2000) Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16:145-171. Rosen ED, Spiegelman BM (2001) PPARγ: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276:37731-37734. Rosen ED (2002) The molecular control of adipogenesis, with special reference to lymphatic pathology. Ann N Y Acad Sci 979:143-158; discussion 188-196. Rubin CS, Hirsch A, Fung C, Rosen OM (1978) Development of hormone receptors and hormonal responsiveness in vitro. Insulin receptors and insulin sensitivity in the preadipocyte and adipocyte forms of 3T3-L1 cells. J Biol Chem 253:7570-7578. Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B. (2004) Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 145:401-406. Sakaue H, Ogawa W, Matsumoto M, Kuroda S, Takata M, Sugimoto T, Spiegelman BM, Kasuga M (1998) Posttranscriptional control of adipocyte differentiation through activation of phosphoinositide 3-kinase. J Biol Chem 273:28945-28952. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799-806. Samad F, Yamamoto K, Loskutoff DJ (1996) Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide. J Clin Invest 97:37-46. Samuelsson L, Stromberg K, Vikman K, Bjursell G, Enerback S. (1991) The CCAAT/enhancer binding protein and its role in adipocyte differentiation: evidence for direct involvement in terminal adipocyte development. EMBO J 10:3787-3793. Sasaki T, Kaneko H, Ramamurthy NS, Golub LM (1991) Tetracycline administration restores osteoblast structure and function during experimental diabetes. Anat Rec 231:25-34. Saye JA, Cassis LA, Sturgill TW, Lynch KR, Peach MJ (1989) Angiotensinogen gene expression in 3T3-L1 cells. Am J Physiol 256:C448-451. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746-26749. Schu PV, Takegawa K, Fry MJ, Stack JH, Waterfield MD, Emr SD (1993) Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260:690-693. Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ, Jamal SA, Black DM, Cummings SR (2001) Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 86:32-38. Serrero G, Lepak N (1996) Endocrine and paracrine negative regulators of adipose differentiation. Int J Obes 20, Suppl 3:S58-S64. Song L, Tuan RS (2004) Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow. FASEB J 18:980-982. Sorisky A, Pardasani D, Lin Y (1996) The 3-phosphorylated phosphoinositide response of 3T3-L1 preadipose cells exposed to insulin, insulin-like growth factor-1, or platelet-derived growth factor. Obes Res 4:9-19. Stein GS, Lian JB (1993) Molecular mechanisms mediating proliferation /differentiation interrelationships during progressive development of the osteoblast phenotype. Endocr Rev 14:424-442. Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:537-546. Tomiyama K, Nakata H, Sasa H, Arimura S, Nishio E, Watanabe Y (1995) Wortmannin, a specific phosphatidylinositol 3 kinase inhibitor, inhibits adipocytic differentiation of 3T3-L1 cells. Biochem Biophys Res Commun 212:263-269. Tuominen J, Impivaara O, Puukka P, Ronnenmaa T (1999) Bone mineral density in patients with type 1 and type 2 diabetes. Diabetes Care 22:1196-1200. Umek RM, Friedman AD, McKnight SL. (1991) CCAAT-enhancer binding protein: a component of a differentiation switch. Science 251:288-292. Valius M, Kazlauskas A (1993) Phospholipase c-g1 and phosphatidylinositol 3-kinase are the downstream mediators of the PDGF receptor’s mitogenic signal. Cell 73:321-334. Verhaeghe J, van Herck E, Visser WJ, Suiker AM, Thomasset M, Einhorn TA, Faierman E, Bouillon R (1990) Bone and mineral metabolism in BB rats with long-term diabetes. Decreased bone turnover and osteoporosis. Diabetes 39:477-482. Verhaeghe J, Thomsen JS, van Bree R, van Herck E, Bouillon R, Mosekilde L (2000) Effects of exercise and disuse on bone remodeling, bone mass, and biomechanical competence in spontaneously diabetic female rats. Bone 27:249-256. Verma S, Rajaratnam JH, Denton J, Hoyland JA, Byers RJ (2002) Adipocytic proportion of bone marrow is inversely related to bone formation in osteoporosis. J Clin Pathol 55:693-698. Wakitani S, Saito T, Caplan AI (1995) Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18:1417-1426. Watanabe M, Inukai K, Katagiri H, Awata T, Oka Y, Katayama S (2003) Regulation of PPAR gamma transcriptional activity in 3T3-L1 adipocytes. Biochem Biophys Res Commun 300:429-436. Weinstock R, Goland R, Shane E, Clemens T, Lindsay R, Bilezikian J (1989) Bone mineral density in women with type II diabetes mellitus. J Bone Miner Res 4:97-101. White CB, Turner NS, Lee GC, Haidukewych GJ (2003) Open ankle fractures in patients with diabetes mellitus. Clin Orthop:37-44. Wiske PS, Wentworth SM, Norton JA, Jr., Epstein S, Johnston CC, Jr. (1982) Evaluation of bone mass and growth in young diabetics. Metabolism 31:848-854. Wu Z, Bucher NL, Farmer SR (1996) Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol Cell Biol 16:4128-4136. Wu Z, Puigserver P, Spiegelman BM (1999) Transcriptional activation of adipogenesis. Curr Opin Cell Biol 11:689-694. Yang X, Karsenty G (2002) Transcription factors in bone: developmental and pathological aspects. Trends Mol Med 8:340-345. Yeh WC, Cao Z, Classon M, McKnight SL (1995) Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev 9:168-181. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425-432. Zhu Y, Qi C, Korenberg JR, Chen XN, Noya D, Rao MS, Reddy JK (1995) Structural organization of mouse peroxisome proliferator-activated receptor-γ(mPPAR-γ) gene: alternative promoter use and different splicing yield two mPPAR-γ isoforms. Proc Natl Acad Sci USA 92:7921-7925 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38204 | - |
dc.description.abstract | 糖尿病是指人體內的胰臟不能製造足夠的胰島素或是胰島素失去功能,導致葡萄糖無法充分進入細胞內,使血糖濃度升高,因而形成糖尿病。雖然糖尿病是一種多樣性的症候群,但其基本表現都以高血糖為主。長期處於高血糖狀態會產生一些糖尿病慢性併發症,包括視網膜病變、神經病變、腎臟病變及糖尿病足等等。而糖尿病患者也常出現骨折後骨頭癒合不良的情況,但是糖尿病造成骨質疏鬆的原因尚未釐清。基於骨頭內的間質幹細胞可以分化成造骨細胞及脂肪細胞等等,而且在臨床上也發現隨著年齡的增加,骨頭內的造骨細胞減少,取而代之的是脂肪細胞的增加,進而造成骨質疏鬆症。因此,本篇主要是探討在高血糖狀態下影響間質幹細胞的分化及其相關的分子機制。我們使用25.5mM的高葡萄糖溶液處理間質幹細胞來模擬糖尿病患者的高血糖狀態。
首先,我們證明高葡萄糖會經由phosphoinositide 3-kinase (PI3K)/Akt而促進間質幹細胞分化成脂肪細胞。取6~8週大的FVB/N雄性小鼠的股骨及脛骨,沖出骨髓後培養七天,先單獨處理10-8 M Dexamethasone (DEX) 及 5 μg/ml胰島素,觀察間質幹細胞分化成脂肪細胞的情況。我們發現在第12天脂肪細胞數目明顯的增加,因此在10-8 M DEX 及 5 μg/ml 胰島素下合併處理25.5 mM的高葡萄糖及一個已知會促進脂肪細胞分化的內生性peroxisome proliferators-activated receptor gamma (PPARγ)受質- 15-Deoxy-△12,14-prostaglandin J2 (15d-PGJ2)。12天後以流式細胞儀分析,發現在有25.5 mM的高葡萄糖情況下,脂肪細胞分化的數目比只有處理10-8 M DEX 及 5 μg/ml胰島素的這組增加了1倍,而處理1 μM 15d-PGJ2這組增加了4倍的脂肪細胞。接著,我們探討高葡萄糖促進脂肪細胞分化的機制。在1999年,Wu等人就發現PPARγ這個轉錄因子會調控脂肪細胞的分化。因此,我們合併處理高葡萄糖溶液及15d-PGJ2 12天,發現高葡萄糖溶液及15d-PGJ2會增加PPARγ表現量,而且會被PPARγ拮抗劑- GW 9662 (20 μM) 所抑制。另外,合併處理高葡萄糖溶液及15d-PGJ2也會增加Akt的磷酸化,然而處理PI3K的抑制劑- LY 294002 (7.5 μM) 後,除了會抑制Akt的磷酸化外,也會抑制高葡萄糖溶液及15d-PGJ2促進的PPARγ表現。而且主要是抑制PPARγ的isoform-PPARγ2。由以上的實驗,我們認為高葡萄糖溶液及15d-PGJ2皆會藉由PI3K及Akt這個路徑來促進PPARγ的表現,進而促進脂肪細胞的分化。為了加以確認,我們以轉染作用給予隱性變異質體DN-p85 和 DN-Akt,皆可以減少高葡萄糖溶液及15d-PGJ2促進的PPARγ表現。 由以上實驗,我們認為PI3K/Akt路徑在調控間質幹細胞的分化可能扮演一個很重要的角色。所以,我們更進一步探討PI3K/Akt是否會調控間質幹細胞分化成造骨細胞及其相關的分子機制。我們把沖出的骨髓培養7天後,單獨處理10-8 M DEX,5 μg/ml維他命C及10 mM β-甘油磷酸觀察間質幹細胞分化成造骨細胞的情況。1990年,Owen等人就發現從大鼠的間質幹細胞分化成造骨細胞到造骨細胞死亡的過程需要28天,而在這整個時期,鹼性磷酸酶的活性是屬於早期造骨細胞分化的指標,而骨鈣素的表現及骨礦物質化是屬於晚期的造骨細胞分化指標。而我們的實驗也發現在造骨細胞的分化過程中,第12天的鹼性磷酸酶活性最高,同時合併處理1 μM 15d-PGJ2及25.5 mM 高葡萄糖溶液後,會抑制鹼性磷酸酶的活性,但處理GW 9662 (20 μM) 及LY 294002 (7.5 μM) 後會增加被15d-PGJ2所抑制的鹼性磷酸酶活性,而LY 294002也會增加被高葡萄糖溶液所抑制的鹼性磷酸酶活性。另外我們也觀察造骨細胞分化的晚期指標,發現在第22天骨鈣素的mRNA表現量最大,同時合併處理15d-PGJ2及高葡萄糖後,15d-PGJ2會抑制骨鈣素mRNA的表現,而此現象也會被GW 9662及LY 294002所阻斷,但高葡萄糖溶液則沒有作用。為了加以確認,我們以轉染作用給予隱性變異質體DN-p85 和 DN-Akt,在造骨細胞分化的第22天,發現會抑制15d-PGJ2的作用,進而增加骨礦物質化,但高葡萄糖溶液仍沒有影響。因此,第二部分,我們證明高葡萄糖會經由PI3K/Akt而抑制早期的間質幹細胞分化成造骨細胞。 最後,我們以低劑量streptozotocin (STZ)連續腹腔注射5天,誘導6~8週大的FVB/N雄性小鼠成第一型糖尿病,經過3週後,檢查其血糖是否高於400 mg/dl,沖出控制組及糖尿病組小鼠骨頭內骨髓培養,經過7天後,處理DEX、胰島素及合併高葡萄糖溶液或15d-PGJ2,發現糖尿病組小鼠的間質幹細胞分化成脂肪細胞的比例較控制組高。另外,我們也取控制組及糖尿病組小鼠的脛骨和股骨的骨幹端,大約在生長板的位置,利用液態氮磨碎後,加入溶解緩衝液,測其三酸甘油酯的含量及鹼性磷酸酶的活性,發現糖尿病組小鼠骨頭內的三酸甘油酯含量比控制組小鼠增加1倍,而糖尿病組小鼠的骨頭鹼性磷酸酶活性比控制組小鼠稍低。最後,再利用南方點墨法分析,也發現糖尿病組小鼠的骨頭內PPARγ表現量比控制組高。因此,第三部分,我們證明高血糖的糖尿病小鼠,其骨頭內脂肪組織比控制組多。 綜合以上實驗,我們認為PI3K/Akt在調控間質幹細胞分化上扮演很重要的角色,包括活化PI3K/Akt會增加PPARγ表現進而促進間質幹細胞分化成脂肪細胞,而相反地活化PI3K/Akt會減少鹼性磷酸酶、骨鈣素表現及骨礦物質化進而抑制間質幹細胞分化成造骨細胞。 | zh_TW |
dc.description.abstract | Diabetes is characterized by mild to moderate hyperglycemia, glucosuria, polyphagia, hypoinsulinemia, hyperlipidemia, and weight loss. All forms of diabetes are characterized by chronic hyperglycemia and the development of many serious complications, for example, heart disease (cardiovascular disease), blindness (retinopathy), nerve damage (neuropathy), and kidney damage (nephropathy). Diabetes has also been reported with a net loss of bone. However, the effect of hyperglycemia on bone loss remains unclear. Bone loss in aging and osteoporosis are associated with a decrease in the number and activity of osteoblasts and a parallel increase in the number of adipocytes. Here we have demonstrated that hyperglycemia affected the mesenchymal stem cells (MSCs) differentiation by enhancing adipocyte differentiation (adipogenesis). We used high glucose (HG, 25.5 mM) to mimic the hyperglycemia condition.
To determine the effects of hyperglycemia on adipogenesis, we cultured mouse MSCs in an adipogenic hormonal cocktail, and adipogenesis was strong enhancement by supplementation of HG and 15-deoxy-∆12,14-PGJ2 (15d-PGJ2), which has been identified as an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARγ), inducing adipogenesis in vitro. This ligand improves insulin sensitivity through the activation of the transcription factor, PPARγ. In addition to sensitizing cells to insulin, the PPARγ2 isoform appears to be critical for the regulation of osteoblast differentiation (osteoblastogenesis) and adipocyte differentiation (adipogenesis) of MSCs in bone marrow. In this HG cultures, the expression of PPARγ2 was up-regulated even prior to adipogenic induction. Moreover, treatment with PPARγ agonists, GW 9662 (20 μM) or inhibitors of phosphatidylinositol 3-kinase (PI3K), LY 294002 (7.5 μM), leads to the complete blockade of HG-enhanced adipogenesis of MSCs by inhibited the PPARγ expression. HG-activated Akt on adipogenesis of MSCs was also inhibited by LY 294002. Likewise, blocking the PI3K or Akt activity with the dominant-negative vectors DN-p85 or DN-Akt, respectively, also greatly inhibited the HG-enhanced the expression of PPARγ. These suggesting that HG enhanced adipogenesis of MSCs in the adipogenic medium may through a PI3K/Akt regulated PPARγ pathway. Another intriguing finding was that 15d-PGJ2 (1 μM) enhanced adipogenesis by increasing the PPARγ expression which was inhibited by LY 294002, DN-p85 and DN-Akt. Collectively, these data provide a new insight into the PI3K/Akt pathway on MSCs differentiation. So, next we examine the mechanisms of osteoblastogenesis of MSCs. First, we found that 15d-PGJ2 and HG decreased alkaline phosphatase activity, which was used as early differentiation markers of osteoblastogenesis from MSCs in osteoblastogenic medium, and treatment with GW 9662 or LY294002 was significantly increasing the alkaline phosphatase activity. Second, the 15d-PGJ2 inhibited the expression of the osteocalcin, which gene marked the late stages of osteoblastogenesis, and treatment with GW 9662 or LY294002 was significantly increasing the osteocalcin gene expression. But HG was no effect on osteocalcin expression. Third, mineralization was reduced by treatment of MSCs with 15d-PGJ2 in osteoblastogenic medium and dominant-negative vectors DN-p85 or DN-Akt greatly increased mineralization. HG was also no effect on mineralization. Mineralization correlated closely with osteocalcin gene expression. Taken together, these results indicate that activation of PI3K/Akt pathway in MSCs may increase adipogenesis and decrease osteoblastogenesis of MSCs. On the other hand, in in vivo study, mice were made diabetic by multiple low-dose streptozotocin (STZ) treatment, and controls were treated with vehicle alone. After 3 weeks, chose the diabetic mice which had ≧400 mg/dl blood sugar. We cultured diabetic MSCs and control MSCs in adipogenic medium combined with HG or 15d-PGJ2 and compared their adipogenesis of MSCs. We found that the level of diabetic adipogenesis of MSCs was higher than the level of control mice. Moreover, the tibial bone from the proximal metaphysis to the tibiofibular junction was snap frozen in liquid nitrogen, pulverized, and we found that the expression of PPARγ and triglyceride amounts were significantly increased in the diabetic bone whereas alkaline phosphatase activity was reduced in the diabetic bone. These findings support a reciprocal relationship between the development of bone and fat under hyperglycemia, and may prompt further exploration of the PI3K/Akt regulated MSCs differentiation as a potential target for intervention in diabetic osteoporosis. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T16:27:55Z (GMT). No. of bitstreams: 1 ntu-94-R92447006-1.pdf: 1463798 bytes, checksum: b14c71d12b0aaa03a3d81185933f857f (MD5) Previous issue date: 2005 | en |
dc.description.tableofcontents | CONTENTS…………………………………………………………………………....i
中文摘要………………………...……………….………………………………...….1 ABSTRACT…………………………………………………………………………...4 ABBREVIATIONS…………………………………………………………………....7 CHAPTER Ⅰ INTRODUCTION…………………………………………………….8 1. Diabetes……………………………………………………………………...….8 2. Osteoporosis……………...……………………………………………………11 3. Stem cells………………………………………………………………….......12 4. Adipocyte differentiation (Adipogenesis)……………………………………..13 5. Osteoblast differentiation (Osteoblastogenesis)……………………………….16 6. Specific aims…………………………………………………………………..19 CHAPTER Ⅱ MATERIALS AND METHODS…………………………………….20 CHAPTER Ⅲ RESULTS……………………………………………………………26 1. HG and 15d-PGJ2 enhance adipogenesis of MSCs…………………………….26 2. HG and 15d-PGJ2 enhance adipogenesis of MSCs via increasing the expression of PPARγ……………………………………………………………………….26 3. HG- and 15d-PGJ2-enhanced the PPARγ expression are through the PI3K/Akt pathway………………………..……………………………………………….27 4. HG and 15d-PGJ2 inhibit osteoblastogenesis of MSCs through PI3K/Akt pathway………………………………………………………………………...28 5. Adipocyte markers, PPARγ and triglyceride amount, are increased and osteoblast maker, alkaline phosphatase activity, is decreased in diabetic bone..29 CHAPTER Ⅳ DISCUSSION………………………………………………………..31 FIGURES AND TABLES………..…………………………………………………..38 REFERENCES...…………………...……………………………………...............…59 APPENDICES………………………………………………………………………..69 Figure Ⅰ. Model for the influence of the PPARγ pathway on adipogenesis and osteoblastogenesis. Figure Ⅱ. Dynamic view of the adipocyte, showing signals emanating from white adipose tissue. | |
dc.language.iso | en | |
dc.title | 高血糖狀態調控間質幹細胞分化成脂肪細胞及造骨細胞之機制探討 | zh_TW |
dc.title | Studies on the Mechanisms of Adipocyte and Osteoblast Differentiation from Mesenchymal Stem Cell under Hyperglycemia | en |
dc.type | Thesis | |
dc.date.schoolyear | 93-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 郭明良,蕭水銀,楊榮森 | |
dc.subject.keyword | 間質幹細胞,脂肪細胞分化,造骨細胞分化, | zh_TW |
dc.subject.keyword | hyperglycemia,15-Deoxy-△12,14-prostaglandin J2,mesenchymal stem cell,adipogenesis,osteoblastogenesis,phosphoinositide 3-kinase,peroxisome proliferator-activated receptor gamma, | en |
dc.relation.page | 70 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2005-07-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
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