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.
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References
Thomson AW (1983) Immunobiology of cyclosporin A—a review. Aust J Exp Biol Med Sci 61:147–172
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
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
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
Bennett WH, Norman DJ (1986) Action and toxicity of cyclosporine. Ann Rev Med 37:215–224
Chang JY, Sehgal SN, Bansbach CC (1991) FK506 and rapamycin: novel pharmacological probes of the immune response. Trends Pharm Sci 12:218–223
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
Nisbet NW (1981) Bone absorption and the immune system. Scand J Immunol 4:599–605
Gruber HE (1991) Bone and the immune system. Proc Soc Exp Biol Med 197: 219–225
Stewart PJ, Grean C, Stern PH (1986) Cyclosporin A inhibits calcemic hormone-induced bone resorption in vitro. J Bone Miner Res 1:285–291
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
Stewart PJ, Stern PH (1989) Cyclosporines: correlation of immunosuppressive activity and inhibition of bone resorption. Calcif Tissue Int 45:222–226
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
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
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
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
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
Klein L, Van Jackman K (1976) Assay of bone resorption in vivo with 3H-tetracycline. Calcif Tissue Res 20:275–290
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
Sawchack RJ, Cartier LL (1981) Liquid-chromatographic determination of cyclosporine A in blood and plasma. Clin Chem 27:1368–1370
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
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
Borel JF (1988) Cyclosporin, basic science summary. Transplant Proc 20 (suppl 2):722–730
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
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
Mason J (1990) The pathophysiology of Sandimmune (cyclosporine) in man and animals. I, II. Pediatr Nephrol 4:554–574, 686–704
Ryffel B (1986) Toxicology—Experimental studies. Prog Allergy 38:181–197
Rao A (1991) Signaling mechanisms in T cells. Crit Rev Immunol 10:495–519
Fournier N, Ducet G, Crevat A (1987) Action of cyclosporine on mitochondrial calcium fluxes. J Bioenerg Biomembr 19:297–303
Nagineni CN, Misra BC, Lee DBN, Yanagawa N (1987) Cyclosporine A-calcium channels interaction: a possible mechanism for nephrotoxicity. Transplant Proc 19:1358–1362
Draznin B, Metz SA, Sussman KE, Leitner JW (1988) Cyclosporin-induced inhibition of insulin release. Biochem Pharmacol 37:3941–3945
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
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
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
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
Bennet VJ, Detmar J, Chang L (1991) Growth inhibition by cyclosporin A in vivo and in vitro. Life Sci 48:1455–1461
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
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
Hevesy G (1955) Conservation of skeletal calcium atoms through life. Kgl Danske Vid Selskab Biol Medd 22:1–23
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
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
Klein L (1981) Steady-state relationship of calcium-45 between bone and blood: differences in growing dogs, chicks, and rats. Science 214:190–193
Klein L, Wong KM (1985) Effect of age on bone resorption at the skeletal level in normal humans (abstract) Bone 6:416–417
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
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
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
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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
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DOI: https://doi.org/10.1007/BF00310409