Skip to main content
SpringerLink
Log in

Cyclosporin A does not affect the absolute rate of cortical bone resorption at the organ level in the growing rat

  • Laboratory Investigations
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

The weanling rat, an animal model of rapid bone turnover, was used to evaluate the effects of various doses of cyclosporin A (CsA) on various bones during different time periods. Sprague-Dawley male rats were extensively prelabeled with 3H-tetracycline during 1–3 weeks of age. At 4 weeks of age, four groups of rats were given daily subcutaneous injections: vehicle or CsA—low dose (10 mg/kg), intermediary dose (20 mg/kg), or high dose (30 mg/kg) for 7, 14, or 28 days. Three different whole bones—the femur (low turnover), scapula (moderate turnover), and lumbar-6 vertebra (high turnover) were harvested intact at 4, 5, 6, and 8 weeks of age. The whole bones were assayed weekly for total dry defatted weight, calcium mass (formation), and loss of 3H-tetracycline (bone resorption) following treatment with CsA. Serum CsA levels, calcium creatinine, and alkaline phosphatase were measured weekly. Significant decreases in serum calcium and alkaline phosphatase were observed at 1 and 2 weeks, and were normalized by 4 weeks of treatment. No significant changes in serum creatinine were noted. For all three doses of CsA, no effect was observed on the absolute rate of cortical bone resorption of three different, whole bones over three time periods. Body weight and bone formation in treated animals was significantly smaller in a dose- and time-related fashion compared with control animals at sacrifice. However, compared with the initial control animals, body weights and bone masses of the final treated animals were much larger, suggesting that the smaller bone masses were due to insufficient growth and slow gain in bone mass. Our isotopic data demonstrate that CsA has no effect on the basal rate of bone resorption and decreases rate of bone formation, as observed globally at the whole bone level. Bone measurements at the organ level may lead to different interpretations from those observed at the tissue level.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Thomson AW (1983) Immunobiology of cyclosporin A—a review. Aust J Exp Biol Med Sci 61:147–172

    Google Scholar 

  2. Gunter KC, Irving SG, Zipfel PF, Siebenlist U, Kelly K (1989) Cyclosporin A-mediated inhibition of mitogen-induced gene transcription is specific for the mitogenic stimulus and cell type. J Immunol 142:3286–3291

    Google Scholar 

  3. Granelli-Piperno A, Keane M (1988) Effects of cyclosporine A on T lymphocytes and accessory cells from human blood. Transplant Proc 20 (suppl 2):136–142

    Google Scholar 

  4. Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR (1989) Cyclosporin A specifically inhibits function of nuclear proteins involved in T-cell activation. Science 246: 1617–1620

    Google Scholar 

  5. Bennett WH, Norman DJ (1986) Action and toxicity of cyclosporine. Ann Rev Med 37:215–224

    Google Scholar 

  6. Chang JY, Sehgal SN, Bansbach CC (1991) FK506 and rapamycin: novel pharmacological probes of the immune response. Trends Pharm Sci 12:218–223

    Google Scholar 

  7. Baron R, Vignery A, Horowitz M (1984) Lymphocytes, macrophages and the regulation of bone remodeling. In: Peck WA (ed) Bone and mineral research, Annual 2. Elsevier, Amsterdam, pp 175–243

    Google Scholar 

  8. Nisbet NW (1981) Bone absorption and the immune system. Scand J Immunol 4:599–605

    Google Scholar 

  9. Gruber HE (1991) Bone and the immune system. Proc Soc Exp Biol Med 197: 219–225

    Google Scholar 

  10. Stewart PJ, Grean C, Stern PH (1986) Cyclosporin A inhibits calcemic hormone-induced bone resorption in vitro. J Bone Miner Res 1:285–291

    Google Scholar 

  11. Klaushoffer K, Hoffman O, Stewart PJ, Czerwenka E, Koller K, Peterlik M, Stern PH (1987) Cyclosporin A inhibits bone resorption in cultured neonatal mouse calvaria. J Pharm Exp Ther 23:584–590

    Google Scholar 

  12. Stewart PJ, Stern PH (1989) Cyclosporines: correlation of immunosuppressive activity and inhibition of bone resorption. Calcif Tissue Int 45:222–226

    Google Scholar 

  13. Movsowitz C, Epstein S, Fallon M, Ismail F, Thomas S (1988) Cyclosporin A in vivo produces severe osteopenia in the rat: effect of dose and duration of administration. Endocrinology 123:2571–2577

    Google Scholar 

  14. Katz I, Li M, Joffe I, Stein B, Jacobs T, Liang XG, Ke HZ, Jee WSS, Epstein S (1994) Influence of age on cyclosporin A-induced alterations in bone mineral metabolism in the rat in vivo. J Bone Miner Res 9:59–67

    Google Scholar 

  15. Schlossberg M, Moysowitz C, Epstein S, Ismail F, Fallon MD, Thomas S (1989) The effect of cyclosporin A administration and its withdrawal on bone mineral metabolism in the rat. Endocrinology 124:2179–2183

    Google Scholar 

  16. Orcel P, Bielakoff J, Modrowski D, Miravet L, deVernejoul MC, Denne MA (1989) Cyclosporin A induces in vivo inhibition of resorption and stimulation of formation in rat bone. J Bone Miner Res 4:387–391

    Google Scholar 

  17. Klein L, Li QX, Donovan CA, Powell AE (1990) Variation of resorption rates in vivo of various bones in immature rats. J Bone Miner 8:169–175

    Google Scholar 

  18. Klein L, Van Jackman K (1976) Assay of bone resorption in vivo with 3H-tetracycline. Calcif Tissue Res 20:275–290

    Google Scholar 

  19. Coffey SA, Klein L (1988) Comparison of long bones and vertebrae in growing male rats: rate of growth mineralization, and uptake of 3H-tetracycline at the organ level. Growth Dev Aging 52:151–156

    Google Scholar 

  20. Sawchack RJ, Cartier LL (1981) Liquid-chromatographic determination of cyclosporine A in blood and plasma. Clin Chem 27:1368–1370

    Google Scholar 

  21. Li XQ, Donovan CA, Klein L (1989) A pharmacokinetic model in the rat and rabbit of the direct measurement of mature bone resorption in vivo with 3H-tetracycline. J Pharm Sci 78:823–828

    Google Scholar 

  22. Thomson AW, Whiting PH, Blair JT, Davidson RJL, Simpson JG (1981) Pathological changes developing in the rat during a 3-week course of high dosage cyclosporin A and their reversal following drug withdrawal. Transplantation 32:271–277

    Google Scholar 

  23. Borel JF (1988) Cyclosporin, basic science summary. Transplant Proc 20 (suppl 2):722–730

    Google Scholar 

  24. Blair JT, Thomson AW, Whiting PH, Davidson RJL, Simpson JG (1982) Toxicity of the immune suppressant cyclosporin A in the rat. J Pathol 138:163–178

    Google Scholar 

  25. Ried M, Gibbons S, Kowk D, Van Buren CT, Flechner S, Kahan BD (1983) Cyclosporine levels in human tissues of patients treated for one week to one year. Transplant Proc 15 (suppl 1):2434–2437

    Google Scholar 

  26. Mason J (1990) The pathophysiology of Sandimmune (cyclosporine) in man and animals. I, II. Pediatr Nephrol 4:554–574, 686–704

    Google Scholar 

  27. Ryffel B (1986) Toxicology—Experimental studies. Prog Allergy 38:181–197

    Google Scholar 

  28. Rao A (1991) Signaling mechanisms in T cells. Crit Rev Immunol 10:495–519

    Google Scholar 

  29. Fournier N, Ducet G, Crevat A (1987) Action of cyclosporine on mitochondrial calcium fluxes. J Bioenerg Biomembr 19:297–303

    Google Scholar 

  30. Nagineni CN, Misra BC, Lee DBN, Yanagawa N (1987) Cyclosporine A-calcium channels interaction: a possible mechanism for nephrotoxicity. Transplant Proc 19:1358–1362

    Google Scholar 

  31. Draznin B, Metz SA, Sussman KE, Leitner JW (1988) Cyclosporin-induced inhibition of insulin release. Biochem Pharmacol 37:3941–3945

    Google Scholar 

  32. Pfeilschiffer J, Ruegg UT (1987) Cyclosporin A augments angiotensin II-stimulated rise in intracellular free calcium in vascular smooth muscle cells. Biochem J 248:883–887

    Google Scholar 

  33. Thomson AW, Whiting PH, Cameron ID, Lessels SE, Simpson JG (1981) A toxicological study in rats receiving immunotherapeutic doses of cyclosporin A. Transplantation 31:121–124

    Google Scholar 

  34. Okano K, Yajima M, Yamada Y, Fujibayashi S, Kou S, Sasagawa K, Suzuki S, Naito S, Ohira K, Nawa C, Sakta N, Somagya K (1988) Immunosuppressive agent cyclosporin A and various cell growth factors affect cloned osteoblastic cell line MC3T3-El cells. In: Normal AW et al. (eds) Vitamin D molecular and cellular and clinical endocrinology. Walter de Gruyter, Berlin, pp 608–609

    Google Scholar 

  35. Klein L (1990) Measurements of bone resorption (using 3H-tetracycline), bone formation, and changes in bone mass at the organ level. In: Takahashi HE (ed) Bone morphometry. Nishimura/Smith-Gordon, Niigata, pp 12–20

    Google Scholar 

  36. Bennet VJ, Detmar J, Chang L (1991) Growth inhibition by cyclosporin A in vivo and in vitro. Life Sci 48:1455–1461

    Google Scholar 

  37. del Pozo E, Elford P, Casez JP, Graeber M, Payne T (1990) Effect of Sandimmune on bone remodeling in normal rats and under various pathological conditions. In: Mizashima Y, Amor B (eds) Autoimmunity, rheumatoid arthritis and cyclosporin A. Parthenon, Park Ridge, NJ, pp 53–65

    Google Scholar 

  38. del Pozo E, Graeber M, Elford P, Payne T (1990) Regression of bone and cartilage loss in adjuvant arthritic rats after treatment with cyclosporin A. Arthritis Rheum 33:247–252

    Google Scholar 

  39. Hevesy G (1955) Conservation of skeletal calcium atoms through life. Kgl Danske Vid Selskab Biol Medd 22:1–23

    Google Scholar 

  40. Klein L, Li XQ (1991) Comparison of bone as an organ and as a tissue in young and metabolically mature rats. Cells Materials 1:3–10

    Google Scholar 

  41. Lacroix P, Ponlot R (1958) THe delayed redistribution of radiocalcium in the skeleton. In: Extermann RC (ed) Radioisotopes in scientific research Vol. 4. Pergamon Press, New York, pp 125–131

    Google Scholar 

  42. Klein L (1981) Steady-state relationship of calcium-45 between bone and blood: differences in growing dogs, chicks, and rats. Science 214:190–193

    Google Scholar 

  43. Klein L, Wong KM (1985) Effect of age on bone resorption at the skeletal level in normal humans (abstract) Bone 6:416–417

    Google Scholar 

  44. Horowitz M, Baron R, Mart J, Andreoli M, Vignery A (1985) Osteoclast activating factor is distinct from the monokine IL-1. Br J Rheumatol 24:162–164

    Google Scholar 

  45. Sasagawa K, Fujibayashi S, Okano J, Nawa C, Suzuki S, Kou S, Yamada Y, Someya K (1989) Different inhibitory actions of immunomodulating agents and immunosuppressive agents on bone resorption of mouse calvaria. Int J Immunopharm 11:953–959

    Google Scholar 

  46. Lorenzo JA, Holtrop ME, Raisz LG (1984) Effects of phosphate on calcium release, lysosomal enzyme activity in the medium, and osteoclast morphometry in cultured fetal rat bones. Metab Bone Dis Rel Res 5:187–190

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedics, Case Western Reserve University School of Medicine, 44106, Cleveland, Ohio, USA

    L. Klein, M. S. Lemel, M. S. Wolfe & J. Shaffer

Authors
  1. L. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. S. Lemel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. S. Wolfe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Shaffer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klein, L., Lemel, M.S., Wolfe, M.S. et al. Cyclosporin A does not affect the absolute rate of cortical bone resorption at the organ level in the growing rat. Calcif Tissue Int 55, 295–301 (1994). https://doi.org/10.1007/BF00310409

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00310409

Key words

Search

Navigation