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Enhanced Marrow Adipogenesis and Bone Resorption in Estrogen-Deprived Rats Treated with the PPARgamma Agonist BRL49653 (Rosiglitazone)

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Abstract

Thiazolidinediones are insulin-sensitizing agents and in clinical use for the treatment of type II diabetes. Under specific experimental conditions, these molecules induce adipogenic differentiation of mesenchymal precursor cells at the expense of osteoblasts in vitro, suggesting possible negative effects on the skeleton. We measured effects of the thiazolidinedione BRL49653 on bone tissue of intact and estrogen-deprived skeletally mature adult female Wistar rats (6–9 months old). Weight gain and decreased plasma triglyceride levels confirmed the effectiveness of the treatment. However, no change in bone mass or fat marrow volume was observed in intact rats treated for 8 weeks with 5, 10, or 20 mg/kg of BRL49653. Study of marrow cultures established at necropsy revealed a higher responsiveness to adipogenic differentiation protocols of cultures established from the 10-mg/kg group compared to vehicle control. In a second study, the effects of thiazolidinedione treatment on the skeleton of estrogen-deprived rats were investigated. Application of 10 mg/kg of BRL49653 for 12 weeks resulted in enhanced bone loss (+31%; pQCT) and increased fat marrow volume (+117%; histomorphometry) compared to vehicle-treated OVX control. Interestingly, osteoblast number was comparable in both cases. Bone resorption parameters were significantly increased in the treatment group (+27% osteoclast number, +30% eroded surface). Enhanced bone loss due to treatment was consistently observed in the tibia, femur, and the lumbar spine. Our data indicate that thiazolidinediones may enhance bone loss induced by estrogen deprivation.

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References

  1. HE Lebovitz JF Dole R Patwardhan EB Rappaport MI Freed (2001) ArticleTitleRosiglitazone monotherapy is effective in patients with type 2 diabetes J Clin Endocrinol Metab 86 280–288 Occurrence Handle10.1210/jc.86.1.280 Occurrence Handle1:CAS:528:DC%2BD3MXhtVGnsbo%3D Occurrence Handle11232013

    Article  CAS  PubMed  Google Scholar 

  2. F Picard J Auwerx (2002) ArticleTitlePPAR(gamma) and glucose homeostasis Annu Rev Nutr 22 167–197 Occurrence Handle10.1146/annurev.nutr.22.010402.102808 Occurrence Handle1:CAS:528:DC%2BD38XmtF2htL4%3D Occurrence Handle12055342

    Article  CAS  PubMed  Google Scholar 

  3. JM Lehmann LB Moore TA Smith–Oliver WO Wilkison TM Willson SA Kliewer (1995) ArticleTitleAn antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) J Biol Chem 270 12953–12956 Occurrence Handle10.1074/jbc.270.50.30221 Occurrence Handle1:CAS:528:DyaK2MXmtV2itr0%3D Occurrence Handle7768881

    Article  CAS  PubMed  Google Scholar 

  4. ED Rosen CJ Walkey P Puigserver BM Spiegelman (2000) ArticleTitleTranscriptional regulation of adipogenesis Genes Dev 14 1293–1307 Occurrence Handle1:CAS:528:DC%2BD3cXjvFOgsb8%3D

    CAS  Google Scholar 

  5. TM Willson PJ Brown DD Sternbach BR Henke (2000) ArticleTitleThe PPARs: from orphan receptors to drug discovery J Med Chem 43 527–550 Occurrence Handle1:CAS:528:DC%2BD3cXht1Churk%3D Occurrence Handle10691680

    CAS  PubMed  Google Scholar 

  6. JM Gimble CE Robinson X Wu KA Kelly BR Rodriguez SA Kliewer JM Lehmann DC Morris (1996) ArticleTitlePeroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells Mol Pharmacol 50 1087–1094 Occurrence Handle1:CAS:528:DyaK28XntFCqsrw%3D Occurrence Handle8913339

    CAS  PubMed  Google Scholar 

  7. V Sottile K Seuwen (2000) ArticleTitleBone morphogenetic protein-2 stimulates adipogenic differentiation of mesenchymal precursor cells in synergy with BRL 49653 (rosiglitazone) FEBS Lett 475 201–204

    Google Scholar 

  8. B Lecka–Czemik I Gubrij EJ Moemnan O Kajkenova DA Lipschitz SC Manolagas RL Jilka (1999) ArticleTitleInhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2 J Cell Biochem 74 357–371 Occurrence Handle10.1002/(SICI)1097-4644(19990901)74:3<357::AID-JCB5>3.3.CO;2-Z Occurrence Handle10412038

    Article  PubMed  Google Scholar 

  9. SM Jackson LL Demer (2000) ArticleTitlePeroxisome proliferator-activated receptor activators modulate the osteoblastic maturation of MC3T3-E1 preosteoblasts FEBS Lett 471 119–124

    Google Scholar 

  10. B Lecka–Czernik EJ Moerman DF Grant JM Lehmann SC Manolagas RL Jilka (2002) ArticleTitleDivergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation Endocrinology 143 2376–2384 Occurrence Handle10.1210/en.143.6.2376 Occurrence Handle1:CAS:528:DC%2BD38XjvFKjurg%3D Occurrence Handle12021203

    Article  CAS  PubMed  Google Scholar 

  11. ZC Dang RL Bezooijen Particlevan M Karperien SE Papapoulos CW Lowik (2002) ArticleTitleExposure of KS483 cells to estrogen enhances osteogenesis and inhibits adipogenesis J Bone Miner Res 17 394–405 Occurrence Handle1:CAS:528:DC%2BD38XitVKht78%3D Occurrence Handle11878304

    CAS  PubMed  Google Scholar 

  12. R Okazaki D Inoue M Shibata M Saika S Kido H Ooka H Tomiyama Y Sakamoto T Matsumoto (2002) ArticleTitleEstrogen promotes early osteoblast differentiation and inhibits adipocyte differentiation in mouse bone marrow stromal cell lines that express estrogen receptor (ER) alpha or beta Endocrinology 143 2349–2356 Occurrence Handle10.1210/en.143.6.2349 Occurrence Handle1:CAS:528:DC%2BD38XjvFKjurw%3D Occurrence Handle12021200

    Article  CAS  PubMed  Google Scholar 

  13. X Wang MW Kilgore (2002) ArticleTitleSignal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells Mol Cell Endocrinol 194 123–133 Occurrence Handle10.1016/S0303-7207(02)00154-5 Occurrence Handle1:CAS:528:DC%2BD38XntVaqu74%3D Occurrence Handle12242035

    Article  CAS  PubMed  Google Scholar 

  14. C Jennermann J Triantafillou D Cowan BGA Pennink KM Connolly DC Morris (1995) ArticleTitleEffects of the thiazolidinediones on bone turnover in the rat J Bone Miner Res 10 S241

    Google Scholar 

  15. L Tornvig J Justesen L Mosekilde E Falk M Kassem (2001) ArticleTitleTroglitazone treatment induces bone marrow adipose tissue volume but does not affect trabecular bone volume in mice Calcif Tissue Int 69 46–50 Occurrence Handle10.1007/s002230020018 Occurrence Handle1:CAS:528:DC%2BD3MXmt1egsr0%3D Occurrence Handle11685433

    Article  CAS  PubMed  Google Scholar 

  16. AM Parfitt MK Drezner FH Glorieux JA Kanis H Malluche PJ Meunier SM Ott RR Recker (1987) ArticleTitleBone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee J Bone Miner Res 2 595–610 Occurrence Handle1:STN:280:BieA3sfjsFc%3D Occurrence Handle3455637

    CAS  PubMed  Google Scholar 

  17. V Sottile K Seuwen (2001) ArticleTitleA high-capacity screen for adipogenic differentiation Anal Biochem 293 124–128 Occurrence Handle10.1006/abio.2001.5121 Occurrence Handle1:CAS:528:DC%2BD3MXjslChtL0%3D Occurrence Handle11373088

    Article  CAS  PubMed  Google Scholar 

  18. A Deldar G Williams C Stevens (1993) ArticleTitlePathogenesis of thiazolidinedione-induced hematotoxicity in the dog. Diabetes 42 IssueIDSuppl 179

    Google Scholar 

  19. LM Salamone JA Cauley J Zmuda A Pasagian–Macaulay RS Epstein RE Ferrell DM Black LH Kuller (2000) ArticleTitleApolipoprotein E gene polymorphism and bone loss: estrogen status modifies the influence of apolipoprotein E on bone loss J Bone Miner Res 15 308–314 Occurrence Handle1:CAS:528:DC%2BD3cXhtlGnsrY%3D Occurrence Handle10703933

    CAS  PubMed  Google Scholar 

  20. TJ Wronski LM Dann KS Scott M Cintron (1989) ArticleTitleLong-term effects of ovariectomy and aging on the rat skeleton Calcif Tissue Int 45 360–366 Occurrence Handle1:STN:280:By%2BD38bmslw%3D Occurrence Handle2509027

    CAS  PubMed  Google Scholar 

  21. M Li Y Shen TJ Wronski (1997) ArticleTitleTime course of femoral neck osteopenia in ovariectomized rats Bone 20 55–61 Occurrence Handle10.1016/S8756-3282(96)00317-1 Occurrence Handle1:STN:280:ByiC2c3htFA%3D Occurrence Handle8988348

    Article  CAS  PubMed  Google Scholar 

  22. SC Miller T Wronski (1993) ArticleTitleLong-term osteopenic changes in cancellous bone structure in ovariectomized rats Anat Rec 236 433–444 Occurrence Handle1:STN:280:ByyA2s%2Fmtl0%3D Occurrence Handle8363048

    CAS  PubMed  Google Scholar 

  23. D Benayahu I Shur S Ben-Eliyahu (2001) ArticleTitleHormonal changes affect the bone and bone marrow cells in a rat model J Cell Biochem 79 407–415 Occurrence Handle10.1002/1097-4644(20001201)79:3<407::AID-JCB60>3.0.CO;2-8

    Article  Google Scholar 

  24. R Okazaki M Toriumi S Fukumoto M Miyamoto T Fujita K Tanaka Y Takeuchi (1999) ArticleTitleThiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro Endocrinology 140 5060–5065 Occurrence Handle10.1210/en.140.11.5060 Occurrence Handle1:CAS:528:DyaK1MXmvFemsbc%3D Occurrence Handle10537132

    Article  CAS  PubMed  Google Scholar 

  25. G Mbalaviele Y Abu-Amer A Meng R Jaiswal S Beck MF Pittenger MA Thiede DR Marshak (2000) ArticleTitleActivation of peroxisome proliferator-activated receptor-gamma pathway inhibits osteoclast differentiation J Biol Chem 275 14388–14393 Occurrence Handle10.1074/jbc.275.19.14388 Occurrence Handle1:CAS:528:DC%2BD3cXjt1CnsL0%3D Occurrence Handle10799521

    Article  CAS  PubMed  Google Scholar 

  26. AC Bendixen NK Shevde KM Dienger TM Willson CD Funk JW Pike (2001) ArticleTitleIL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1 Proc Natl Acad Sci U S A 98 2443–2448 Occurrence Handle10.1073/pnas.041493198 Occurrence Handle1:CAS:528:DC%2BD3MXhslKmsr4%3D Occurrence Handle11226258

    Article  CAS  PubMed  Google Scholar 

  27. H Keller F Givel M Perroud W Wahli (1995) ArticleTitleSignaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements Mol Endocrinol 9 794–804 Occurrence Handle10.1210/me.9.7.794 Occurrence Handle1:CAS:528:DyaK2MXms1Knur0%3D Occurrence Handle7476963

    Article  CAS  PubMed  Google Scholar 

  28. SO Rzonca D Suva DC Gaddy B Montague B Lecka–Czemik (2004) ArticleTitleBone is a target for the antidiabetic compound rosiglitazone Endocrinology 145 401–406 Occurrence Handle10.1210/en.2003-0746 Occurrence Handle1:CAS:528:DC%2BD3sXhtVWgtL7O Occurrence Handle14500573

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Anne Studer, Margot Brüderlin, and Reto Cortesi are gratefully acknowledged for their essential contributions to the in vivo aspects of this study. We thank Barbara Wilmering for support in cell culture.

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Correspondence to K. Seuwen or M. Kneissel.

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Sottile, V., Seuwen, K. & Kneissel, M. Enhanced Marrow Adipogenesis and Bone Resorption in Estrogen-Deprived Rats Treated with the PPARgamma Agonist BRL49653 (Rosiglitazone). Calcif Tissue Int 75, 329–337 (2004). https://doi.org/10.1007/s00223-004-0224-8

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