Calcified Tissue International

, Volume 75, Issue 4, pp 329–337 | Cite as

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

Article

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.

Keywords

Diabetes Osteoporosis Cell differentiation Osteoblast Adipocyte 

Notes

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.

References

  1. 1.
    Lebovitz, HE, Dole, JF, Patwardhan, R, Rappaport, EB, Freed, MI 2001Rosiglitazone monotherapy is effective in patients with type 2 diabetesJ Clin Endocrinol Metab86280288CrossRefPubMedGoogle Scholar
  2. 2.
    Picard, F, Auwerx, J 2002PPAR(gamma) and glucose homeostasisAnnu Rev Nutr22167197CrossRefPubMedGoogle Scholar
  3. 3.
    Lehmann, JM, Moore, LB, Smith–Oliver, TA, Wilkison, WO, Willson, TM, Kliewer, SA 1995An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)J Biol Chem2701295312956CrossRefPubMedGoogle Scholar
  4. 4.
    Rosen, ED, Walkey, CJ, Puigserver, P, Spiegelman, BM 2000Transcriptional regulation of adipogenesisGenes Dev1412931307Google Scholar
  5. 5.
    Willson, TM, Brown, PJ, Sternbach, DD, Henke, BR 2000The PPARs: from orphan receptors to drug discoveryJ Med Chem43527550PubMedGoogle Scholar
  6. 6.
    Gimble, JM, Robinson, CE, Wu, X, Kelly, KA, Rodriguez, BR, Kliewer, SA, Lehmann, JM, Morris, DC 1996Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cellsMol Pharmacol5010871094PubMedGoogle Scholar
  7. 7.
    Sottile, V, Seuwen, K 2000Bone morphogenetic protein-2 stimulates adipogenic differentiation of mesenchymal precursor cells in synergy with BRL 49653 (rosiglitazone)FEBS Lett475201204Google Scholar
  8. 8.
    Lecka–Czemik, B, Gubrij, I, Moemnan, EJ, Kajkenova, O, Lipschitz, DA, Manolagas, SC, Jilka, RL 1999Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2J Cell Biochem74357371CrossRefPubMedGoogle Scholar
  9. 9.
    Jackson, SM, Demer, LL 2000Peroxisome proliferator-activated receptor activators modulate the osteoblastic maturation of MC3T3-E1 preosteoblastsFEBS Lett471119124Google Scholar
  10. 10.
    Lecka–Czernik, B, Moerman, EJ, Grant, DF, Lehmann, JM, Manolagas, SC, Jilka, RL 2002Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiationEndocrinology14323762384CrossRefPubMedGoogle Scholar
  11. 11.
    Dang, ZC, Bezooijen, RL, Karperien, M, Papapoulos, SE, Lowik, CW 2002Exposure of KS483 cells to estrogen enhances osteogenesis and inhibits adipogenesisJ Bone Miner Res17394405PubMedGoogle Scholar
  12. 12.
    Okazaki, R, Inoue, D, Shibata, M, Saika, M, Kido, S, Ooka, H, Tomiyama, H, Sakamoto, Y, Matsumoto, T 2002Estrogen promotes early osteoblast differentiation and inhibits adipocyte differentiation in mouse bone marrow stromal cell lines that express estrogen receptor (ER) alpha or betaEndocrinology14323492356CrossRefPubMedGoogle Scholar
  13. 13.
    Wang, X, Kilgore, MW 2002Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cellsMol Cell Endocrinol194123133CrossRefPubMedGoogle Scholar
  14. 14.
    Jennermann, C, Triantafillou, J, Cowan, D, Pennink, BGA, Connolly, KM, Morris, DC 1995Effects of the thiazolidinediones on bone turnover in the ratJ Bone Miner Res10S241(abstract)Google Scholar
  15. 15.
    Tornvig, L, Justesen, J, Mosekilde, L, Falk, E, Kassem, M 2001Troglitazone treatment induces bone marrow adipose tissue volume but does not affect trabecular bone volume in miceCalcif Tissue Int694650CrossRefPubMedGoogle Scholar
  16. 16.
    Parfitt, AM, Drezner, MK, Glorieux, FH, Kanis, JA, Malluche, H, Meunier, PJ, Ott, SM, Recker, RR 1987Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature CommitteeJ Bone Miner Res2595610PubMedGoogle Scholar
  17. 17.
    Sottile, V, Seuwen, K 2001A high-capacity screen for adipogenic differentiationAnal Biochem293124128CrossRefPubMedGoogle Scholar
  18. 18.
    Deldar, A, Williams, G, Stevens, C 1993Pathogenesis of thiazolidinedione-induced hematotoxicity in the dog.Diabetes42179(abstract)Google Scholar
  19. 19.
    Salamone, LM, Cauley, JA, Zmuda, J, Pasagian–Macaulay, A, Epstein, RS, Ferrell, RE, Black, DM, Kuller, LH 2000Apolipoprotein E gene polymorphism and bone loss: estrogen status modifies the influence of apolipoprotein E on bone lossJ Bone Miner Res15308314PubMedGoogle Scholar
  20. 20.
    Wronski, TJ, Dann, LM, Scott, KS, Cintron, M 1989Long-term effects of ovariectomy and aging on the rat skeletonCalcif Tissue Int45360366PubMedGoogle Scholar
  21. 21.
    Li, M, Shen, Y, Wronski, TJ 1997Time course of femoral neck osteopenia in ovariectomized ratsBone205561CrossRefPubMedGoogle Scholar
  22. 22.
    Miller, SC, Wronski, T 1993Long-term osteopenic changes in cancellous bone structure in ovariectomized ratsAnat Rec236433444PubMedGoogle Scholar
  23. 23.
    Benayahu, D, Shur, I, Ben-Eliyahu, S 2001Hormonal changes affect the bone and bone marrow cells in a rat modelJ Cell Biochem79407415CrossRefGoogle Scholar
  24. 24.
    Okazaki, R, Toriumi, M, Fukumoto, S, Miyamoto, M, Fujita, T, Tanaka, K, Takeuchi, Y 1999Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitroEndocrinology14050605065CrossRefPubMedGoogle Scholar
  25. 25.
    Mbalaviele, G, Abu-Amer, Y, Meng, A, Jaiswal, R, Beck, S, Pittenger, MF, Thiede, MA, Marshak, DR 2000Activation of peroxisome proliferator-activated receptor-gamma pathway inhibits osteoclast differentiationJ Biol Chem2751438814393CrossRefPubMedGoogle Scholar
  26. 26.
    Bendixen, AC, Shevde, NK, Dienger, KM, Willson, TM, Funk, CD, Pike, JW 2001IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1Proc Natl Acad Sci U S A9824432448CrossRefPubMedGoogle Scholar
  27. 27.
    Keller, H, Givel, F, Perroud, M, Wahli, W 1995Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elementsMol Endocrinol9794804CrossRefPubMedGoogle Scholar
  28. 28.
    Rzonca, SO, Suva, D, Gaddy, DC, Montague, B, Lecka–Czemik, B 2004Bone is a target for the antidiabetic compound rosiglitazoneEndocrinology145401406CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Novartis Institutes for Biomedical ResearchNovartis Pharma AGBaselSwitzerland
  2. 2.Institute of Genetics, University of NottinghamQueen’s Medical CenterNottinghamUK

Personalised recommendations