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Journal of Bone and Mineral Metabolism

, Volume 24, Issue 3, pp 199–205 | Cite as

High-turnover osteoporosis is induced by cyclosporin A in rats

  • Chie Wada
  • Masatoshi KataokaEmail author
  • Hiroyuki Seto
  • Noriko Hayashi
  • Jun-ichi Kido
  • Yasuo Shinohara
  • Toshihiko Nagata
ORIGINAL ARTICLE

Abstract

Cyclosporin A (CsA) is used widely as an immunosuppressive agent, but it induces osteoporosis as a prominent side effect. To elucidate the mechanisms involved in CsA-induced osteoporosis, the effects of CsA on bone metabolism were investigated in a rat experimental model. Fifteen-day-old rats were fed a powdered diet containing or lacking CsA for 8–30 days. Analysis was performed by micro-computed tomography (μCT) and light microscopy to examine histomorphometric changes in rat tibiae on days 8, 16, and 30. Plasma parathyroid hormone (PTH) and osteocalcin (OCN) levels were determined by enzyme-linked immunosorbent assay (ELISA) on days 8, 16, and 30. The expression of OCN, osteopontin (OPN), and cathepsin K mRNAs in tibial bone marrow was examined by Northern blot analysis on days 8 and 16. Although no significant differences were observed in tibial length during the experimental periods, or in histomorphometric parameters on day 8, an apparent decrease in bone volume was observed in the CsA-treated group after day 16. Histologic analysis showed that the number of osteoblasts and osteoclasts on the surface of trabecular bone in the CsA-treated group had increased significantly on day 16. Plasma PTH and OCN levels in CsA-treated rats were significantly higher than those in control animals on day 8. Northern blot analysis revealed that the CsA-treated group showed an increase in the expression of OCN, OPN, and cathepsin K mRNAs on day 8 compared with the controls. These findings suggest that bone resorption in CsA-treated rats is induced by high-turnover osteoporosis and that bone remodeling activity may be activated by PTH.

Key words

cyclosporin A osteoporosis μCT parathyroid hormone 

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References

  1. 1.
    Shevach, EM 1985The effects of cyclosporin A on the immune systemAnnu Rev Immunol3397423CrossRefPubMedGoogle Scholar
  2. 2.
    Farthing, MJ, Clark, ML 1981Nature of the toxicity of cyclosporin A in the ratBiochem Pharmacol3033113316CrossRefPubMedGoogle Scholar
  3. 3.
    Daley, TD, Wysocki, GP 1984Cyclosporine therapy. Its significance to the periodontistJ Periodontol55708712PubMedGoogle Scholar
  4. 4.
    Bartold, PM 1987Cyclosporine and gingival overgrowthJ Oral Pathol16463468PubMedGoogle Scholar
  5. 5.
    Rodino, MA, Shane, E 1998Osteoporosis after organ transplantationAm J Med104459469CrossRefPubMedGoogle Scholar
  6. 6.
    Epstein, S 1996Post-transplantation bone disease: the role of immunosuppressive agents and the skeletonJ Bone Miner Res1117PubMedGoogle Scholar
  7. 7.
    Cueto-Manzano, AM, Konel, S, Hutchinson, AJ, Crowley, V, France, MW, Freemont, AJ, Adams, JE, Mawer, B, Gokal, R 1999Bone loss in long-term renal transplantation: histopathology and densitometry analysisKidney Int5520212029CrossRefPubMedGoogle Scholar
  8. 8.
    Durieux, S, Mercadal, L, Orcel, P, Dao, H, Rioux, C, Bernald, M, Rozenberg, S, Barrou, B, Bourgeois, P, Deray, G, Bagnis, CI 2002Bone mineral density and fracture prevalence in long-term kidney graft recipientsTransplantation74496500PubMedGoogle Scholar
  9. 9.
    Compston, JE 2003Osteoporosis after liver transplantationLiver Transpl9321330PubMedGoogle Scholar
  10. 10.
    Meeran, K, Hattersley, A, Burrin, J, Shiner, R, Ibbertson, K 1995Oral and inhaled corticosteroids reduce bone formation as shown by plasma osteocalcin levelsAm J Respir Crit Care Med151333336PubMedGoogle Scholar
  11. 11.
    King, CS, Weir, EC, Gundberg, CW, Fox, J, Insogna, KL 1996Effects of continuous glucocorticoid infusion on bone metabolism in the ratCalcif Tissue Int59184191CrossRefPubMedGoogle Scholar
  12. 12.
    Stewart, PJ, Green, OC, Stern, PH 1986Cyclosporine A inhibits calcemic hormone-induced bone resorption in vitroJ Bone Miner Res1285291PubMedGoogle Scholar
  13. 13.
    Movsowitz, C, Epstein, S, Fallon, M, Ismail, F, Thomas, S 1988Cyclosporin-A in vivo produces severe osteopenia in the rat: effect of dose and duration of administrationEndocrinology12325712577PubMedGoogle Scholar
  14. 14.
    Orcel, P, Bielakoff, J, Modrowski, D, Miravet, L, de Vernejoul, MC 1989Cyclosporin A induces in vivo inhibition of resorption and stimulation of formation in rat boneJ Bone Miner Res4387391PubMedGoogle Scholar
  15. 15.
    Klein, L, Lemel, MS, Wolfe, MS, Shaffer, J 1994Cyclosporin A does not affect the absolute rate of cortical bone resorption at the organ level in the growing ratCalcif Tissue Int55295301CrossRefPubMedGoogle Scholar
  16. 16.
    Kataoka, M, Shimizu, Y, Kunikiyo, K, Asahara, Y, Yamashita, K, Ninomiya, M, Morisaki, I, Ohsaki, Y, Kido, J, Nagata, T 2000Cyclosporin A decreases the degradation of type I collagen in rat gingival overgrowthJ Cell Physiol182351358CrossRefPubMedGoogle Scholar
  17. 17.
    Morisaki, I, Kitamura, K, Kato, K, Marukawa, Y, Mihara, J 1993Age dependency of cyclosporin A-induced gingival overgrowth in ratsPediatr Dent15414417PubMedGoogle Scholar
  18. 18.
    Waarsing, JH, Day, JS, van der Linden, JC, Ederveen, AG, Spanjers, C, De Clerck, N, Sasov, A, Verhaar, JA, Weinans, H 2004Detecting and tracking local changes in the tibiae of individual rats: a novel method to analyse longitudinal in vivo micro-CT dataBone34163169CrossRefPubMedGoogle Scholar
  19. 19.
    Fleet, JC, Hock, JM 1994Identification of osteocalcin mRNA in nonosteoid tissue of rats and humans by reverse transcription-polymerase chain reactionJ Bone Miner Res915651573PubMedGoogle Scholar
  20. 20.
    Huang, W, Rudkin, GH, Carlsen, B, Ishida, K, Ghasri, P, Anvar, B, Yamaguchi, DT, Miller, TA 2002Overexpression of BMP-2 modulates morphology, growth, and gene expression in osteoblastic cellsExp Cell Res274226234CrossRefPubMedGoogle Scholar
  21. 21.
    Komine, M, Kukita, A, Kukita, T, Ogata, Y, Hotokebuchi, T, Kohashi, O 2001Tumor necrosis factor-α cooperates with receptor activator of nuclear factor kB ligand in generation of osteoblasts in stromal cell-depleted rat bone marrow cell cultureBone28474483CrossRefPubMedGoogle Scholar
  22. 22.
    Nishikawa, S, Nagata, T, Morisaki, I, Oka, T, Ishida, H 1996Pathogenesis of drug-induced gingival overgrowth. A review of studies in the rat modelJ Periodontol67463471PubMedGoogle Scholar
  23. 23.
    Schlosberg, M, Movsowitz, C, Epstein, S, Ismal, F, Fallon, MD, Thomas, S 1989The effect of cyclosporin A administration and its withdrawal on bone mineral metabolism in the ratEndocrinology12421792184PubMedGoogle Scholar
  24. 24.
    Compston, JE, Greer, S, Skingle, SJ, Stirling, DM, Price, C, Friend, PJ, Alexander, G 1996Early increase in plasma parathyroid hormone levels following liver transplantationJ Hepatol25715718CrossRefPubMedGoogle Scholar
  25. 25.
    Giannini, S, D'Angelo, A, Carraro, G, Antonello, A, Di Landro, D, Marchini, F, Plebani, M, Zaninotto, M, Rigotti, P, Sartori, L, Crepaldi, G 2001Persistently increased bone turnover and low bone density in long-term survivors of kidney transplantationClin Nephrol56353363PubMedGoogle Scholar
  26. 26.
    Epstein, S, Dissanayake, IR, Goodman, GR, Bowman, AR, Zhou, H, Ma, Y, Jee, WS 2001Effect of the interaction of parathyroid hormone and cyclosporine A on bone mineral metabolism in the ratCalcif Tissue Int68240247CrossRefPubMedGoogle Scholar
  27. 27.
    Seto, H, Aoki, K, Kasugai, S, Ohya, K 1999Trabecular bone turnover, bone marrow cell development, and gene expression of bone matrix proteins after low calcium feeding in ratsBone25687695CrossRefPubMedGoogle Scholar
  28. 28.
    Stein, B, Halloran, BP, Reinhardt, T, Engstrom, GW, Bales, CW, Drezner, MK, Currie, KL, Takizawa, M, Adams, JS, Epstein, S 1991Cyclosporin-A increases synthesis of 1, 25-dihydroxyvitamin D3 in the rat and mouseEndocrinology12813691373PubMedGoogle Scholar
  29. 29.
    Silver, J, Yalcindag, C, Sela-Brown, A, Kilav, R, Naveh-Many, T 1999Regulation of the parathyroid hormone gene by vitamin D, calcium and phosphateKidney Int Suppl73S2S7PubMedGoogle Scholar
  30. 30.
    Holtrop, ME, King, GJ, Cox, KA, Reit, B 1979Time-related changes in the ultrastructure of osteoclasts after injection of parathyroid hormone in young ratsCalcif Tissue Int27129135PubMedGoogle Scholar
  31. 31.
    von Stechow, D, Zurakowski, D, Pettit, AR, Muller, R, Gronowicz, G, Chorev, M, Out, H, Libermann, T, Alexander, JM 2004Differential transcriptional effects of PTH and estrogen during anabolic bone formationJ Cell Biochem93476490CrossRefPubMedGoogle Scholar
  32. 32.
    Zaidi, M, Troen, B, Moonga, BS, Abe, E 2001Cathepsin K, osteoclastic resorption, and osteoporosis therapyJ Bone Miner Res1617471749PubMedGoogle Scholar
  33. 33.
    Nagata, T, Goldberg, HA, Zhang, Q, Domenicucci, C, Sodek, J 1991Biosynthesis of bone proteins by fetal porcine calvariae in vitro. Rapid association of sulfated sialoproteins (secreted phosphoprotein-1 and bone sialoprotein) and chondroitin sulfate proteoglycan (CS-PGIII) with bone mineralMatrix1186100PubMedGoogle Scholar
  34. 34.
    Yao, KL, Todescan, R,Jr, Sodek, J 1994Temporal changes in matrix protein synthesis and mRNA expression during mineralized tissue formation by adult rat bone marrow cells in cultureJ Bone Miner Res9231240PubMedGoogle Scholar
  35. 35.
    Ikedo, D, Ohishi, K, Yamauchi, N, Kataoka, M, Kido, J, Nagata, T 1999Stimulatory effects of phenytoin on osteoblastic differentiation of fetal rat calvaria cells in cultureBone25653660CrossRefPubMedGoogle Scholar
  36. 36.
    Barling, PM, Bibby, NJ 1985Study of the localization of [3H]bovine parathyroid hormone in bone by light microscope autoradiographyCalcif Tissue Int37441446PubMedGoogle Scholar
  37. 37.
    Irie, K, Ozawa, H 1996Immunohistochemical location of parathyroid hormone/parathyroid hormone-related peptide receptor in rat tibiaeJ Bone Miner Metab141014CrossRefGoogle Scholar
  38. 38.
    Kirino, S, Fukunaga, J, Ikegami, S, Tsuboi, H, Kimata, M, Nakata, N, Nakano, M, Ueno, T, Mizukawa, N, Sugahara, T 2004Regulation of bone metabolism in immunosuppressant (FK506)-treated ratJ Bone Miner Metab22554560CrossRefPubMedGoogle Scholar
  39. 39.
    Kobayashi, Y, Ueyama, S, Arai, Y, Yoshida, Y, Kaneda, T, Sato, T, Shin, K, Kumegawa, M, Hakeda, Y 2004The active metabolite of leflunomide, A771726, inhibits both the generation of and the bone-resorbing activity of osteoclasts by acting directly on cells of the osteoclast lineageJ Bone Miner Metab22318328CrossRefPubMedGoogle Scholar
  40. 40.
    Bartlett, RR, Schleyerbach, R 1985Immunopharmacological profile of a novel isoxazol derivative, HWA486, with potential antirheumatic activity. 1. Disease modifying action on adjuvant arthritis of the ratInt J Immunopharmacol7718PubMedGoogle Scholar
  41. 41.
    Ueyama, S, Arai, Y, Yoshida, Y, Kitagawa, H, Inazu, N, Yaguchi, M 1999Leflunomide inhibits loss of bone mineral density and the reduction of bone mechanical strength in rats with adjuvant-induced arthritisAnn Rheum Dis59144Google Scholar
  42. 42.
    Herrman, M, Schleyerbach, R, Kirschbaum, BJ 2000Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseasesImmunopharmacology47273289Google Scholar
  43. 43.
    Knecht, W, Loffler, M 1998Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivativesBiochem Pharmacol5612591264CrossRefPubMedGoogle Scholar
  44. 44.
    Liu, J, Farmer, JD, Lane, WS, Friedman, J, Weissman, I, Schreiber, SL 1991Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexesCell66807815CrossRefPubMedGoogle Scholar
  45. 45.
    O'Keefe, SJ, Tamura, J, Kincaid, RL, Tocci, MJ, O'Neill, EA 1992FK506 and CsA sensitive activation of the interleukin-2 promoter by calcineurinNature357692694CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2006

Authors and Affiliations

  • Chie Wada
    • 1
    • 2
  • Masatoshi Kataoka
    • 1
    Email author
  • Hiroyuki Seto
    • 2
  • Noriko Hayashi
    • 2
  • Jun-ichi Kido
    • 2
  • Yasuo Shinohara
    • 1
    • 3
    • 4
  • Toshihiko Nagata
    • 2
  1. 1.Division of Gene Expression, Institute for Genome ResearchThe University of TokushimaTokushimaJapan
  2. 2.Department of Periodontology and Endodontology, Institute of Health BioscienceThe University of Tokushima Graduate SchoolTokushimaJapan
  3. 3.Faculty of Pharmaceutical SciencesThe University of TokushimaTokushimaJapan
  4. 4.Health Technology Research CenterNational Institute of Advanced Industrial Science and Technology (AIST)TakamatsuJapan

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