Skip to main content

Advertisement

SpringerLink
Log in

Short-term systemic insulin-like growth factor-1 is unable to prevent cyclosporin A-induced osteopenia in the rat

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

Abstract

Immunosuppression with cyclosporin A (CsA) is effective in a number of immune-mediated diseases and in preventing rejection following organ transplantation. We have repeatedly demonstrated that CsA in the rat model produces accelerated bone remodelling with net bone loss, best characterized in trabecular bone. IGF-I holds promise as a treatment for various osteopenic conditions. Although currently a subject of much controversy, various studies have suggested thatin vivo it is anabolic to cortical as well as trabecular bone. The purpose of this study was, in part, to further characterize the effects of CsA and IGF-I on trabecular and cortical bone, and to see whether systemic IGF-I is able to modulate CsA’s deleterious skeletal effects. Sixty 10 week-old, male, Sprague-Dawley rats were randomized to receive the following daily for 3 weeks: (1) CsA vehicle (veh) per os (po) + recombinant human (rh) IGF-1 veh subcutaneously (sc); (2) CsA 15 mg/kg po + rhIGF-I-veh; (3) CsA-veh + rhIGF-I 200 µg/kg sc; (4) CsA-veh + rhIGF-I 600 (µg/kg sc; (5) CsA 15 mg/kg + rhIGF-I 200 µg/kg, and (6) CsA 15 mg/kg + rhIGF-I 600 (xg/kg. Rats were weighed and venous blood was sampled serially for determination of glucose, ionized calcium (Ca2+), PTH, vitamin D, and osteocalcin. Following sacrifice on day 20, histomorphometry was performed on double calcein-labeled tibial metaphysis and diaphysis. All rats receiving CsA had elevated levels of blood glucose and osteocalcin by day 9 and vitamin D at day 20. PTH was similar in all groups, and Ca2+ was only raised in the CsA and CsA + IGF-I 200 |xg/kg groups. Rats receiving IGF-I 200 jxg/kg and IGF-I 600 fxg/kg gained more weight than either vehicle-or CsA-treated animals, attesting to IGF-1’s anabolic properties. CsA caused severe trabecular bone loss, not prevented by IGF-I; it even further increased the eroded surface. CsA and IGF-I had little effect on cortical bone volume or marrow area. IGF-I increased endocortical matrix synthesis, as evidenced by the increases in the percent endocortical osteoid perimeter, an effect negated by the addition of CsA. This experiment demonstrates that trabecular bone is more susceptible than cortical bone to the deleterious effects of CsA and indicates little role for IGF-1 in the pathophysiology or treatment of CsA-induced bone disease at the given doses and duration of treatment.

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. Joffe I, Katz I, Sehgal S, et al. (1993) Lack of change of cancellous bone volume with short-term use of the new immunosuppresent rapamycin in rats. Calcif Tissue Int 53:45–52

    Article  PubMed  CAS  Google Scholar 

  2. Keown PA, Stiller CR (1987) Cyclosporine: a double-edged sword. Hosp Prac 22:207–220

    CAS  Google Scholar 

  3. Movsowitz C, Epstein S, Ismail F, Fallon M, Thomas S (1989) Cyclosporin A in the oophorectomized rat: unexpected severe bone resorption. J Bone Miner Res 4:393–398

    PubMed  CAS  Google Scholar 

  4. 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

    PubMed  CAS  Google Scholar 

  5. Aubia J, Masramon J, Serrano S, Lloveras J, Marinoso LL (1988) Bone histology in renal transplant patients receiving cyclosoporin. Lancet 1:1048–1049

    Article  Google Scholar 

  6. Shane E, Rivas MDC, Silverberg SJ, Kim TS, Staron RB, Bilezikian JP (1993) Osteoporosis after cardiac transplantation. Am J Med 94:257–264

    Article  PubMed  CAS  Google Scholar 

  7. Sambrook PN, Kelly PJ, Fontana D, et al. (1994) Mechanisms of rapid bone loss following cardiac transplantation. Osteoporosis Int 4:273–276

    Article  CAS  Google Scholar 

  8. Froesch ER, Schmid C, Schwander J, Zapf J (1985) Actions of insulin-like growth factors. Ann Rev Physiol 47:443

    Article  CAS  Google Scholar 

  9. Schlechter NL, Russell SM, Spencer EM, Nicoll CS (1986) Evidence suggesting that the direct growth-promoting effect of growth hormone on cartilage in vivo is mediated by local production of somatomedin. Proc Natl Acad Soc USA 83: 7932

    Article  CAS  Google Scholar 

  10. Watson P, Lazowski D, Han V, Fraher L, Steer B, Hodsman A (1995) Parathyroid hormone restores bone mass and enhances osteoblast insulin-like growth factor 1 gene expression in ovariectomized rats. Bone 16(3):357–365

    Article  PubMed  CAS  Google Scholar 

  11. Canalis E, Centrella M, Burch W, McCarthy TL (1989) Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 83:60–65

    PubMed  CAS  Google Scholar 

  12. McCarthy TL, Centrella M, Raisz LG, Canalis E (1991) Prostaglandin E2 stimulates insulin-like growth factor 1 synthesis in osteoblast-enriched cultures from fetal rat bone. Endocrinology 128:2895–2900

    PubMed  CAS  Google Scholar 

  13. Canalis E, Pash J, Gabbitas B, Rydziel S, Varghese S (1993) Growth factors regulate the synthesis of insulin-like growth factor-1 in bone cell cultures. Endocrinology 133:33–38

    Article  PubMed  CAS  Google Scholar 

  14. McCarthy TL, Centrella M, Canalis E (1989) Regulatory effects of insulin-like growth factors 1 and 11 on bone collagen synthesis in rat calvarial cultures. Endocrinology 124:301–309

    PubMed  CAS  Google Scholar 

  15. Hock JM, Centrella M, Canalis E (1988) Insulin-like growth factor-1 (IGF-1) has independent effects on bone matrix formation and cell replication. Endocrinology 122:254–260

    PubMed  CAS  Google Scholar 

  16. Mochizuki H, Hakeda Y, Wakatsuki N, et al. (1992) Insulinlike growth factor-I supports formation and activation of osteoclasts. Endocrinology 131:1075–1080

    Article  PubMed  CAS  Google Scholar 

  17. Canalis E (1994) (editorial) Skeletal growth factors and aging. J Clin Endocrinol Metab 78(5): 1009–1010

    Article  PubMed  CAS  Google Scholar 

  18. Tobias JH, Chow JWM, Chambers TJ (1992) Opposite effects of insulin-like growth factor-1 on the formation of trabecular and cortical bone in adult female rats. Endocrinology 131: 2387–2392

    Article  PubMed  CAS  Google Scholar 

  19. Ibbotson KJ, Orcutt CM, D’Souza SM, et al. (1992) Contrasting effects of parathyroid hormone and insulin-like growth factor 1 in an aged ovariectomized rat model of postmenopausal osteoporosis. J Bone Miner Res 7:425–432

    PubMed  CAS  Google Scholar 

  20. Spencer EM, Liu CC, Si ECC, Howard GA (1991) In vivo actions of insulin-like growth factor-1 (IGF-1) on bone formation and resorption in rats. Bone 12:21–26

    Article  PubMed  CAS  Google Scholar 

  21. Kalu DN Liu CC, Salerno E, et al. (1991) Insulin-like growth factor-] partially prevents ovariectomy-induced bone loss: a comparative study with human parathyroid hormone (1-38). J Bone Miner Res 6:S221

    Google Scholar 

  22. Mueller K, Cortesi R (1991) Insulin-like growth factor-1 increases trabecular bone mass on the ovariectomised rat. J Bone Miner Res 6:S221

    Google Scholar 

  23. Shapiro JR, Rachis R, Bellantoni M, Harman SM, Blackman MR (1993) The effect of IGF-1 on skeletal turnover in postmenopausal women. J Bone Miner Res 8:S327

    Google Scholar 

  24. Ebeling PR, Jones JD, O’Fallon WM, Janes CH, Riggs BL (1993) Short-term effects of recombinant human insulin-like growth factor I on bone turnover in normal women. J Clin Endocrinol Metab 77(5): 1384–1387

    Article  PubMed  CAS  Google Scholar 

  25. Beschorner WE, Divic J, Pulido H, Yao X, Ken worthy P, Bruce G (1991) Enhancement of thymic recovery after cyclosporine by recombinant human growth hormone and insulin-like growth factor-1. Transplantation 52:879–884

    Article  PubMed  CAS  Google Scholar 

  26. Price PA, Parthemore JG, Deftos LJ (1980) New biochemical marker for bone metabolism: measurement by radioimmunoassay of bone gla protein in the plasma of normal subjects and patients with bone disease. J Clin Invest 66:878

    Article  PubMed  CAS  Google Scholar 

  27. Rucinski B, Mann GN, Epstein S (1995) A new rapid and reproducible homologous immunoradiometric assay for amino-terminal parathyroid hormone in the rat. Calcif Tissue Int 56:83–87

    Article  PubMed  CAS  Google Scholar 

  28. Reinhardt TA, Horst RL, Orf JW, Hollis BW (1986) A microassay for 1,25-dihydroxyvitamin D not requiring high performance liquid chromatography: application to a clinical studies. J Clin Endocrinol Metabl 58:91–98

    Google Scholar 

  29. Jee WSS, Inoue J, Jee KW, Haba T (1983) Histomorphometric assay of the growing long bone. In: Takahashi H (ed) Handbook of bone morphology. Nishimura Co., Ltd., Niigata City, pp 101–122

    Google Scholar 

  30. Li XJ, Jee WSS, Ke HZ, Mori S, Akamine T (1992) Agerelated changes of cancellous and cortical bone histomorphometry in female Sprague-Dawley rats. Cells Materials (suppl)l:25–35

    Google Scholar 

  31. Jee WSS, Ke HZ, Li XJ, Long-term anabolic effect of prostaglandin E2 on tibial diaphyseal bone in male rats. Bone Miner (1991)15:33–55

    Article  PubMed  CAS  Google Scholar 

  32. Parfitt AM, Drezner MK, Glorieux FH, et al. (1987) Bone histomorphometry: standardization of nomenclature, symbols and units. Report of the ASBMR Histomorphometry Committee. J Bone Miner Res 2:595–610

    PubMed  CAS  Google Scholar 

  33. Brommage R, Millerman E, Sweett E, DeLeon E, Adams S, Bagi CM (1993) Treatment with the rhIGF-l/IGFBP-3 complex increases cortical bone and lean body mass in ovariectomized rats. J Bone Miner Res (supp 1)8:S134

    Google Scholar 

  34. Clemmons DR, Smith-Banks A, Underwood LE (1992) Reversal of diet-induced catabolism by infusion of recombinant insulin-like growth factor-1 in humans. J Clin Endocrinol Metab 75(l):234–238

    Article  PubMed  CAS  Google Scholar 

  35. Guler HP, Zapf J, Scheiwiller E, Froesch ER (1988) Recombinant human insulin-like growth factor-1 stimulates growth and has distinctive efffects on organ size in hypophysectomized rats. Proc Natl Acad Sci USA 85:4889–4893

    Article  PubMed  CAS  Google Scholar 

  36. Hizuka N, Takano K, Shizume K (1986) IGF-1 stimulates growth in normal growing rats. Eur J of Pharmacol 125:143–146

    Article  CAS  Google Scholar 

  37. Romero DF, Buchinsky FJ, Rucinski B, et al. (1995) Rapamycin: a bone-sparing immunosuppressant? J Bone Miner Res 10(5):760–768

    PubMed  CAS  Google Scholar 

  38. Helmchen U, Schmidt WE, Siegel E, Creutzfeldt W (1984) Morphological and functional changes in pancreatic B cells in cyclosporin A-treated rats. Diabetologia 27:416–418

    Article  PubMed  CAS  Google Scholar 

  39. Stein B, Halloran BP, Reinhardt G, et al. (1991) Cyclosporin-A increases synthesis of 1,25 dihydroxyvitamin D3 in the rat and mouse. Endocrinology 128:1369–1373

    PubMed  CAS  Google Scholar 

  40. Schlosberg M, Movsowitz C, Epstein S, Fallon MD, Thomas S (1989) The effect of cyclosporin A administration and its withdrawal on bone mineral metabolism in the rat. Endocrinology 124:2179–2184

    PubMed  CAS  Google Scholar 

  41. Jacobs TW, Katz IA, Joffe II, Stein B, Takizawa M, Epstein S (1991) The effect of FK 506, cyclosporine A, and cyclosporine G on serum 1,25 dihydroxyvitamin D3 levels. Trans Proc 23(6):3188–3189

    CAS  Google Scholar 

  42. Yoon K, Rutledge SJC, Buenaga RF, Rodan GA (1988) Characterization of the rat osteocalcin gene: stimulation of promoter activity by 1,25-dihydroxyvitamin D3. Biochemistry 27:8521–8526

    Article  PubMed  CAS  Google Scholar 

  43. Ismail F, Epstein S, Fallon MD, Thomas SB, Reinhardt TA (1988) Serum bone gla protein and the vitamin D endocrine system in the oophorectomized rat. Endocrinology 122:624–630

    Article  PubMed  CAS  Google Scholar 

  44. Jacobs TW, Epstein S (1992) Current status of serum-derived bone proteins. In: Davidovitch Z (ed) The biological mechanisms of tooth movement and craniofacial adaptation. Ohio State University College of Dentistry, Columbus, 149–158

    Google Scholar 

  45. Klein L, Lemel MS, Wolfe MS, Shaffer J (1994) CsA does not affect the absolute rate of cortical bone resorption at the organ level in the growing rat. Calcif Tissue Int 55:295–301

    Article  PubMed  CAS  Google Scholar 

  46. Bagi CM, Brommage R, Deleon L, Adams S, Rosen D, Sommer A (1994) Benefit of systemically administered rhIGF-1/ GFBP-3 on cancellous bone in ovariectomized rats. J Bone Miner Res 9(8): 1301–1312

    Article  PubMed  CAS  Google Scholar 

  47. Canalis E (1993) Systemic and local factors and the maintenance of bone quality. Calcif Tissue Int 53(supp 1):S9O-S93

    Google Scholar 

  48. Bagi C, Van Der Meulen M, Brommage R, Rosen D, Sommer A (1995) The effect of systemically administered rhIGF-1/ IGFBP-3 complex on cortical bone strength and structure in ovariectomized rats. Bone 16(5):559–565

    Article  PubMed  CAS  Google Scholar 

  49. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R (1993) Anabolic actions of parathyroid hormone on bone. Endocr Rev 14(6):690–709

    Article  PubMed  CAS  Google Scholar 

  50. Kupfer SR, Underwood LE, Baxter RC, Clemmons DR (1993) Enhancement of the anabolic effects of GH and IGF-1 by use of both agents simultaneously. J Clin Invest 91:391–396

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Medicine, Albert Einstein Medical Center, 5401 Old York Rd., 19141, Philadelphia, Pennsylvania, USA

    H. P. Bryer, B. Rucinski & S. Epstein

  2. Division of Radiobiology, Building 586, University of Utah, 84112, Salt Lake City, Utah

    H. K. Chen, Y. F. Ma & W. S. S. Jee

Authors
  1. G. N. Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. A. Sass
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. K. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. J. Buchinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. P. Bryer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. F. Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W. S. S. Jee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B. Rucinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. Epstein
    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

Mann, G.N., Sass, D.A., Chen, H.K. et al. Short-term systemic insulin-like growth factor-1 is unable to prevent cyclosporin A-induced osteopenia in the rat. Calcif Tissue Int 59, 38–44 (1996). https://doi.org/10.1007/s002239900083

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s002239900083

Key words

Search

Navigation