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Journal of Biomedicine and Biotechnology
Volume 2011 (2011), Article ID 903097, 8 pages
http://dx.doi.org/10.1155/2011/903097
Review Article

Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children

1Sansom Institute for Health Research, and School of Pharmacy and Medical Sciences, University of South Australia, City East Campus, GPO Box 2471, Adelaide, SA 5001, Australia
2Discipline of Paediatrics, University of Adelaide, Adelaide, SA 5005, Australia
3Discipline of Physiology, University of Adelaide, Adelaide, SA 5005, Australia

Received 10 September 2010; Accepted 21 January 2011

Academic Editor: Andrea Vecchione

Copyright © 2011 Chiaming Fan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. H. M. Kronenberg, “Developmental regulation of the growth plate,” Nature, vol. 423, no. 6937, pp. 332–336, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. D. B. Pateder, R. A. Eliseev, R. J. O'Keefe et al., “The role of autocrine growth factors in radiation damage to the epiphyseal growth plate,” Radiation Research, vol. 155, no. 6, pp. 847–857, 2001. View at Scopus
  3. H. Robson, “Bone growth mechanisms and the effects of cytotoxic drugs,” Archives of Disease in Childhood, vol. 81, no. 4, pp. 360–364, 1999. View at Scopus
  4. B. C. J. van der Eerden, M. Karperien, and J. M. Wit, “Systemic and local regulation of the growth plate,” Endocrine Reviews, vol. 24, no. 6, pp. 782–801, 2003. View at Publisher · View at Google Scholar · View at Scopus
  5. J. Wang, J. Zhou, C. M. Cheng, J. J. Kopchick, and C. A. Bondy, “Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth,” Journal of Endocrinology, vol. 180, no. 2, pp. 247–255, 2004. View at Publisher · View at Google Scholar · View at Scopus
  6. O. Nilsson, D. Chrysis, O. Pajulo et al., “Localization of estrogen receptors-α and -β and androgen receptor in the human growth plate at different pubertal stages,” Journal of Endocrinology, vol. 177, no. 2, pp. 319–326, 2003. View at Publisher · View at Google Scholar · View at Scopus
  7. J. Ophoff, K. Venken, F. Callewaert, S. Boonen, R. Bouillon, and D. Vanderschueren, “Sex steroids during bone growth: a comparative study between mouse models for hypogonadal and senile osteoporosis,” Osteoporosis International, vol. 20, no. 10, pp. 1749–1757, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. K. Venken, F. Callewaert, S. Boonen, and D. Vanderschueren, “Sex hormones, their receptors and bone health,” Osteoporosis International, vol. 19, no. 11, pp. 1517–1525, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. C. J. Xian, “Roles of epidermal growth factor family in the regulation of postnatal somatic growth,” Endocrine Reviews, vol. 28, no. 3, pp. 284–296, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. D. Chen, M. Zhao, and G. R. Mundy, “Bone morphogenetic proteins,” Growth Factors, vol. 22, no. 4, pp. 233–241, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. T. A. Linkhart, S. Mohan, and D. J. Baylink, “Growth factors for bone growth and repair: IGF, TGFβ and BMP,” Bone, vol. 19, no. 1, pp. 1S–12S, 1996. View at Publisher · View at Google Scholar · View at Scopus
  12. P. Ammann, S. Bourrin, J. P. Bonjour, J. M. Meyer, and R. Rizzoli, “Protein undernutrition-induced bone loss is associated with decreased IGF-I levels and estrogen deficiency,” Journal of Bone and Mineral Research, vol. 15, no. 4, pp. 683–690, 2000. View at Scopus
  13. A. L. Bueno and M. A. Czepielewski, “The importance for growth of dietary intake of calcium and vitamin D,” Jornal de Pediatria, vol. 84, no. 5, pp. 386–394, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. C. C. Johnston, J. Z. Miller, C. W. Slemenda et al., “Calcium supplementation and increases in bone mineral density in children,” The New England Journal of Medicine, vol. 327, no. 2, pp. 82–87, 1992. View at Scopus
  15. C. H. Pui, L. L. Robison, and A. T. Look, “Acute lymphoblastic leukaemia,” The Lancet, vol. 371, no. 9617, pp. 1030–1043, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. M. Abromowitch, J. Ochs, C. H. Pui, D. Fairclough, S. B. Murphy, and G. K. Rivera, “Efficacy of high-dose methotrexate in childhood acute lymphocytic leukemia: analysis by contemporary risk classifications,” Blood, vol. 71, no. 4, pp. 866–869, 1988. View at Scopus
  17. N. J. Minaur, C. Jefferiss, A. K. Bhalla, and J. N. Beresford, “Methotrexate in the treatment of rheumatoid arthritis. I. In vitro effects on cells of the osteoblast lineage,” Rheumatology, vol. 41, no. 7, pp. 735–740, 2002. View at Scopus
  18. B. N. Cronstein, “Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis,” Pharmacological Reviews, vol. 57, no. 2, pp. 163–172, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. N. Boukhettala, J. Leblond, S. Claeyssens et al., “Methotrexate induces intestinal mucositis and alters gut protein metabolism independently of reduced food intake,” American Journal of Physiology, vol. 296, no. 1, pp. E182–E190, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. M. Sosin and S. Handa, “Lesson of the week: low dose methotrexate and bone marrow suppression,” British Medical Journal, vol. 326, no. 7383, pp. 266–267, 2003. View at Scopus
  21. W. Högler, G. Wehl, T. van Staa, B. Meister, A. Klein-Franke, and G. Kropshofer, “Incidence of skeletal complications during treatment of childhood acute lymphoblastic leukemia: comparison of fracture risk with the general practice research database,” Pediatric Blood and Cancer, vol. 48, no. 1, pp. 21–27, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. I. M. van der Sluis, M. M. van den Heuvel-Eibrink, K. Hählen, E. P. Krenning, and S. M. P. F. De Muinck Keizer-Schrama, “Altered bone mineral density and body composition, and increased fracture risk in childhood acute lymphoblastic leukemia,” Journal of Pediatrics, vol. 141, no. 2, pp. 204–210, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. P. M. Crofton, S. F. Ahmed, J. C. Wade et al., “Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 9, pp. 3121–3129, 1998. View at Publisher · View at Google Scholar · View at Scopus
  24. J. M. Halton, S. A. Atkinson, L. Fraher et al., “Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia,” Journal of Bone and Mineral Research, vol. 11, no. 11, pp. 1774–1783, 1996. View at Scopus
  25. K. Mandel, S. Atkinson, R. D. Barr, and P. Pencharz, “Skeletal morbidity in childhood acute lymphoblastic leukemia,” Journal of Clinical Oncology, vol. 22, no. 7, pp. 1215–1221, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. J. M. Halton, S. A. Atkinson, and R. D. Barr, “Growth and body composition in response to chemotherapy in children with acute lymphoblastic leukemia,” International Journal of Cancer, vol. 78, no. 11, pp. 81–84, 1998. View at Scopus
  27. M. B. Viana and M. I. Vilela, “Height deficit during and many years after treatment for acute lymphoblastic leukemia in children: a review,” Pediatric Blood and Cancer, vol. 50, no. 2, pp. 509–516, 2008. View at Publisher · View at Google Scholar · View at PubMed
  28. B. L. van Leeuwen, W. A. Kamps, R. M. Hartel, R. P. H. Veth, W. J. Sluiter, and H. J. Hoekstra, “Effect of single chemotherapeutic agents on the growing skeleton of the rat,” Annals of Oncology, vol. 11, no. 9, pp. 1121–1126, 2000. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Walsh, G. R. Jordan, C. Jefferiss, K. Stewart, and J. N. Beresford, “High concentrations of dexamethasone suppress the proliferation but not the differentiation or further maturation of human osteoblast precursors in vitro: relevance to glucocorticoid-induced osteoporosis,” Rheumatology, vol. 40, no. 1, pp. 74–83, 2001. View at Scopus
  30. W. S. Jee and W. Yao, “Overview: animal models of osteopenia and osteoporosis,” Journal of Musculoskeletal and Neuronal Interactions, vol. 1, no. 3, pp. 193–207, 2001.
  31. M. B. Leonard, “Glucocorticoid-induced osteoporosis in children: impact of the underlying disease,” Pediatrics, vol. 119, no. 2, pp. S166–S174, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. H. Robson, E. Anderson, O. B. Eden, O. Isaksson, and S. Shalet, “Chemotherapeutic agents used in the treatment of childhood malignancies have direct effects on growth plate chondrocyte proliferation,” Journal of Endocrinology, vol. 157, no. 2, pp. 225–235, 1998. View at Publisher · View at Google Scholar · View at Scopus
  33. B. L. van Leeuwen, R. M. Hartel, H. W. B. Jansen, W. A. Kamps, and H. J. Hoekstra, “The effect of chemotherapy on the morphology of the growth plate and metaphysis of the growing skeleton,” European Journal of Surgical Oncology, vol. 29, no. 1, pp. 49–58, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. C. Fan, J. C. Cool, M. A. Scherer et al., “Damaging effects of chronic low-dose methotrexate usage on primary bone formation in young rats and potential protective effects of folinic acid supplementary treatment,” Bone, vol. 44, no. 1, pp. 61–70, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. C. J. Xian, J. C. Cool, M. A. Scherer et al., “Cellular mechanisms for methotrexate chemotherapy-induced bone growth defects,” Bone, vol. 41, no. 5, pp. 842–850, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. C. J. Xian, J. C. Cool, M. A. Scherer, C. Fan, and B. K. Foster, “Folinic acid attenuates methotrexate chemotherapy-induced damages on bone growth mechanisms and pools of bone marrow stromal cells,” Journal of Cellular Physiology, vol. 214, no. 3, pp. 777–785, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. O. S. Nilsson, F. C. H. Bauer, L. A. Brostrom, and U. Nilsonne, “Effect of the antineoplastic agent methotrexate on experimental heterotopic new bone formation in rats,” Cancer Research, vol. 44, no. 4, pp. 1653–1656, 1984. View at Scopus
  38. D. L. Wheeler, R. A. Vander Griend, T. J. Wronski, G. J. Miller, E. E. Keith, and J. E. Graves, “The short- and long-term effects of methotrexate on the rat skeleton,” Bone, vol. 16, no. 2, pp. 215–221, 1995. View at Publisher · View at Google Scholar · View at Scopus
  39. K. P. May, D. Mercill, M. T. McDermott, and S. G. West, “The effect of methotrexate on mouse bone cells in culture,” Arthritis and Rheumatism, vol. 39, no. 3, pp. 489–494, 1996. View at Publisher · View at Google Scholar · View at Scopus
  40. D. Benayahu, “The osteogenic compartment of bone marrow: cell biology and clinical application,” Hematology, vol. 4, no. 5, pp. 427–435, 2000. View at Scopus
  41. A. Banfi, M. Podestà, L. Fazzuoli et al., “High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia,” Cancer, vol. 92, no. 9, pp. 2419–2428, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. J. H. Davies, B. A. J. Evans, M. E. M. Jenney, and J. W. Gregory, “In vitro effects of combination chemotherapy on osteoblasts: implications for osteopenia in childhood malignancy,” Bone, vol. 31, no. 2, pp. 319–326, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. J. Li, H. K. W. Law, L. L. Yu, and G. C. F. Chan, “Differential damage and recovery of human mesenchymal stem cells after exposure to chemotherapeutic agents,” British Journal of Haematology, vol. 127, no. 3, pp. 326–334, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. L. P. Mueller, J. Luetzkendorf, T. Mueller, K. Reichelt, H. Simon, and H. J. Schmoll, “Presence of mesenchymal stem cells in human bone marrow after exposure to chemotherapy: evidence of resistance to apoptosis induction,” Stem Cells, vol. 24, no. 12, pp. 2753–2765, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. S. P. Hauser, K. B. Udupa, and D. A. Lipschitz, “Murine marrow stromal response to myelotoxic agents in vitro,” British Journal of Haematology, vol. 95, no. 4, pp. 596–604, 1996. View at Scopus
  46. C. N. Bennett, K. A. Longo, W. S. Wright et al., “Regulation of osteoblastogenesis and bone mass by Wnt10b,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 9, pp. 3324–3329, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. C. E. Macsai, B. K. Foster, and C. J. Xian, “Roles of Wnt signalling in bone growth, remodelling, skeletal disorders and fracture repair,” Journal of Cellular Physiology, vol. 215, no. 3, pp. 578–587, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. K. R. Georgiou, B. K. Foster, and C. J. Xian, “Damage and recovery of the bone marrow microenvironment induced by cancer chemotherapy—potential regulatory role of chemokine CXCL12/receptor CXCR4 signalling,” Current Molecular Medicine, vol. 10, no. 5, pp. 440–453, 2010. View at Publisher · View at Google Scholar
  49. M. Nesbit, W. Krivit, R. Heyn, and H. Sharp, “Acute and chronic effects of methotrexate on hepatic, pulmonary, and skeletal systems,” Cancer, vol. 37, supplement 2, pp. 1048–1057, 1976. View at Scopus
  50. K. P. May, S. G. West, M. T. McDermott, and W. E. Huffer, “The effect of low-dose methotrexate on bone metabolism and histomorphometry in rats,” Arthritis and Rheumatism, vol. 37, no. 2, pp. 201–206, 1994. View at Scopus
  51. G. E. Friedlaender, R. B. Tross, and A. C. Doganis, “Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model,” Journal of Bone and Joint Surgery. American, vol. 66, no. 4, pp. 602–607, 1984. View at Scopus
  52. H. Hayashi, K. I. Nakahama, T. Sato et al., “The role of Mac-1 (CD11b/CD18) in osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand,” FEBS Letters, vol. 582, no. 21-22, pp. 3243–3248, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. M. Darst, M. Al-Hassani, T. Li et al., “Augmentation of chemotherapy-induced cytokine production by expression of the platelet-activating factor receptor in a human epithelial carcinoma cell line,” Journal of Immunology, vol. 172, no. 10, pp. 6330–6335, 2004. View at Scopus
  54. W. J. Boyle, W. S. Simonet, and D. L. Lacey, “Osteoclast differentiation and activation,” Nature, vol. 423, no. 6937, pp. 337–342, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. E. M. Dennisona, C. Coopera, and Z. A. Colea, “Early development and osteoporosis and bone health,” Journal of Developmental Origins of Health and Disease, vol. 1, pp. 142–149, 2010.