New understanding of glucocorticoid action in bone cells

  • Kim, Hyun-Ju (Skeletal Diseases Genome Research Center, Department of Medicine, Kyungpook National University School of Medicine)
  • 투고 : 2010.07.06
  • 발행 : 2010.08.31


Glucocorticoids (GCs) are useful drugs for the treatment of various diseases, but their use for prolonged periods can cause severe side effects such as osteoporosis. GCs have a direct effect on bone cells, where they can arrest bone formation, in part through the inhibition of osteoblast. On the other hand, GCs potently suppress osteoclast resorptive activity by disrupting its cytoskeleton based on the inhibition of RhoA, Rac and Vav3 in response to macrophage colony-stimulating factor. GCs also interfere with microtubule distribution and stability, which are critical for cytoskeletal organization in osteoclasts. Thus, GCs inhibit microtubule-dependent cytoskeletal organization in osteoclasts, which, in the context of bone remodeling, further dampens bone formation.




  1. Manolagas, S. C. and Weinstein, R. S. (1999) New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J. Bone Miner Res. 14, 1061-1066.
  2. Weinstein, R. S. (2001) Glucocorticoid-induced osteoporosis. Rev. Endocr. Metab. Disord. 2, 65-73.
  3. Lukert, B. P. and Raisz, L. G. (1990) Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann. Intern. Med. 112, 352-364.
  4. Canalis, E., Bilezikian, J. P., Angeli, A. and Giustina, A. (2004) Perspectives on glucocorticoid-induced osteoporosis. Bone 34, 593-598.
  5. Luengo, M., Picado, C., Piera, C., Guanabens, N., Montserrat, J. M., Rivera, J. and Setoain, J. (1991) Intestinal calcium absorption and parathyroid hormone secretion in asthmatic patients on prolonged oral or inhaled steroid treatment. Eur. Respir. J. 4, 441-444.
  6. Paz-Pacheco, E., Fuleihan, G. E. and LeBoff, M. S. (1995) Intact parathyroid hormone levels are not elevated in glucocorticoid-treated subjects. J. Bone Miner Res. 10, 1713-1718.
  7. Hollenberg, S. M., Weinberger, C., Ong, E. S., Cerelli, G., Oro, A., Lebo, R., Thompson, E. B., Rosenfeld, M. G. and Evans, R. M. (1985) Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318, 635-641.
  8. Miesfeld, R., Okret, S., Wikstrom, A. C., Wrange, O., Gustafsson, J. A. and Yamamoto, K. R. (1984) Characterization of a steroid hormone receptor gene and mRNA in wildtype and mutant cells. Nature 312, 779-781.
  9. Kumar, R. and Thompson, E. B. (2005) Gene regulation by the glucocorticoid receptor: structure: function relationship. J. Steroid. Biochem. Mol. Biol. 94, 383-394.
  10. Reichardt, H. M. and Schutz, G. (1998) Glucocorticoid signalling--multiple variations of a common theme. Mol. Cell Endocrinol. 146, 1-6.
  11. Ruppert, S., Boshart, M., Bosch, F. X., Schmid, W., Fournier, R. E. and Schutz, G. (1990) Two genetically defined transacting loci coordinately regulate overlapping sets of liver-specific genes. Cell 61, 895-904.
  12. Drouin, J., Sun, Y. L., Chamberland, M., Gauthier, Y., De Lean, A., Nemer, M. and Schmidt, T. J. (1993) Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J. 12, 145-156.
  13. Stromstedt, P. E., Poellinger, L., Gustafsson, J. A. and Carlstedt-Duke, J. (1991) The glucocorticoid receptor binds to a sequence overlapping the TATA box of the human osteocalcin promoter: a potential mechanism for negative regulation. Mol. Cell Biol. 11, 3379-3383.
  14. Li, C., Li, Y., Liu, H., Sun, Z., Lu, J. and Zhao, Y. (2008) Glucocorticoid repression of human with-no-lysine (K) kinase-4 gene expression is mediated by the negative response elements in the promoter. J. Mol. Endocrinol. 40, 3-12.
  15. Liberman, A. C., Druker, J., Perone, M. J. and Arzt, E. (2007) Glucocorticoids in the regulation of transcription factors that control cytokine synthesis. Cytokine Growth Factor Rev. 18, 45-56.
  16. Liberman, A. C., Druker, J., Refojo, D., Holsboer, F. and Arzt, E. (2009) Glucocorticoids inhibit GATA-3 phosphorylation and activity in T cells. FASEB J. 23, 1558-1571.
  17. Liberman, A. C., Refojo, D., Druker, J., Toscano, M., Rein, T., Holsboer, F. and Arzt, E. (2007) The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. FASEB J. 21, 1177-1188.
  18. Ogawa, S., Lozach, J., Benner, C., Pascual, G., Tangirala, R. K., Westin, S., Hoffmann, A., Subramaniam, S., David, M., Rosenfeld, M. G. and Glass, C. K. (2005) Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122, 707-721.
  19. Weinstein, R. S., Jilka, R. L., Parfitt, A. M. and Manolagas, S. C. (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J. Clin. Invest. 102, 274-282.
  20. Espina, B., Liang, M., Russell, R. G. and Hulley, P. A. (2008) Regulation of bim in glucocorticoid-mediated osteoblast apoptosis. J. Cell Physiol. 215, 488-496.
  21. Kogianni, G., Mann, V., Ebetino, F., Nuttall, M., Nijweide, P., Simpson, H. and Noble, B. (2004) Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis. Life Sci. 75, 2879-2895.
  22. Liu, Y., Encinas, M., Comella, J. X., Aldea, M. and Gallego, C. (2004) Basic helix-loop-helix proteins bind to TrkB and p21(Cip1) promoters linking differentiation and cell cycle arrest in neuroblastoma cells. Mol. Cell Biol. 24, 2662-2672.
  23. O'Brien, C. A., Jia, D., Plotkin, L. I., Bellido, T., Powers, C. C., Stewart, S. A., Manolagas, S. C. and Weinstein, R. S. (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145, 1835-1841.
  24. Smith, E., Coetzee, G. A. and Frenkel, B. (2002) Glucocorticoids inhibit cell cycle progression in differentiating osteoblasts via glycogen synthase kinase-3beta. J. Biol. Chem. 277, 18191-18197.
  25. Canalis, E. (1996) Clinical review 83: mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J. Clin. Endocrinol. Metab. 81, 3441-3447.
  26. Pereira, R. C., Delany, A. M. and Canalis, E. (2002) Effects of cortisol and bone morphogenetic protein-2 on stromal cell differentiation: correlation with CCAAT-enhancer binding protein expression. Bone 30, 685-691.
  27. Pereira, R. M., Delany, A. M. and Canalis, E. (2001) Cortisol inhibits the differentiation and apoptosis of osteoblasts in culture. Bone 28, 484-490.
  28. Ito, S., Suzuki, N., Kato, S., Takahashi, T. and Takagi, M. (2007) Glucocorticoids induce the differentiation of a mesenchymal progenitor cell line, ROB-C26 into adipocytes and osteoblasts, but fail to induce terminal osteoblast differentiation. Bone 40, 84-92.
  29. Pereira, R. C., Delany, A. M. and Canalis, E. (2004) CCAAT/enhancer binding protein homologous protein (DDIT3) induces osteoblastic cell differentiation. Endocrinology 145, 1952-1960.
  30. Wu, Z., Bucher, N. L. and Farmer, S. R. (1996) Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol. Cell Biol. 16, 4128-4136.
  31. Aubin, J. E. (1999) Osteoprogenitor cell frequency in rat bone marrow stromal populations: role for heterotypic cell-cell interactions in osteoblast differentiation. J. Cell Biochem. 72, 396-410.<396::AID-JCB9>3.0.CO;2-6
  32. Eijken, M., Koedam, M., van Driel, M., Buurman, C. J., Pols, H. A. and van Leeuwen, J. P. (2006) The essential role of glucocorticoids for proper human osteoblast differentiation and matrix mineralization. Mol. Cell Endocrinol. 248, 87-93.
  33. Purpura, K. A., Aubin, J. E. and Zandstra, P. W. (2004) Sustained in vitro expansion of bone progenitors is cell density dependent. Stem Cells 22, 39-50.
  34. Teitelbaum, S. L. (2000) Bone resorption by osteoclasts. Science 289, 1504-1508.
  35. Hofbauer, L. C., Gori, F., Riggs, B. L., Lacey, D. L., Dunstan, C. R., Spelsberg, T. C. and Khosla, S. (1999) Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140, 4382-4389.
  36. Rubin, J., Biskobing, D. M., Jadhav, L., Fan, D., Nanes, M. S., Perkins, S. and Fan, X. (1998) Dexamethasone promotes expression of membrane-bound macrophage colony-stimulating factor in murine osteoblast-like cells. Endocrinology 139, 1006-1012.
  37. Dempster, D. W. (1989) Bone histomorphometry in glucocorticoid-induced osteoporosis. J. Bone Miner Res. 4, 137-141.
  38. Prummel, M. F., Wiersinga, W. M., Lips, P., Sanders, G. T. and Sauerwein, H. P. (1991) The course of biochemical parameters of bone turnover during treatment with corticosteroids. J. Clin. Endocrinol. Metab. 72, 382-386.
  39. Kim, Y. H., Jun, J. H., Woo, K. M., Ryoo, H. M., Kim, G. S. and Baek, J. H. (2006) Dexamethasone inhibits the formation of multinucleated osteoclasts via down-regulation of beta3 integrin expression. Arch. Pharm. Res. 29, 691-698.
  40. Kim, H. J., Zhao, H., Kitaura, H., Bhattacharyya, S., Brewer, J. A., Muglia, L. J., Ross, F. P. and Teitelbaum, S. L. (2006) Glucocorticoids suppress bone formation via the osteoclast. J. Clin. Invest. 116, 2152-2160.
  41. Jia, D., O'Brien, C. A., Stewart, S. A., Manolagas, S. C. and Weinstein, R. S. (2006) Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 147, 5592-5599.
  42. Weinstein, R. S., Chen, J. R., Powers, C. C., Stewart, S. A., Landes, R. D., Bellido, T., Jilka, R. L., Parfitt, A. M. and Manolagas, S. C. (2002) Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J. Clin. Invest. 109, 1041-1048.
  43. Teitelbaum, S. L. (2007) Osteoclasts: what do they do and how do they do it? Am. J. Pathol. 170, 427-435.
  44. Teitelbaum, S. L. and Ross, F. P. (2003) Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638-649.
  45. Faccio, R., Novack, D. V., Zallone, A., Ross, F. P. and Teitelbaum, S. L. (2003) Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by beta3 integrin. J. Cell Biol. 162, 499-509.
  46. Nakamura, I., Kadono, Y., Takayanagi, H., Jimi, E., Miyazaki, T., Oda, H., Nakamura, K., Tanaka, S., Rodan, G. A. and Duong le, T. (2002) IL-1 regulates cytoskeletal organization in osteoclasts via TNF receptor-associated factor 6/c-Src complex. J. Immunol. 168, 5103-5109.
  47. Sakai, H., Chen, Y., Itokawa, T., Yu, K. P., Zhu, M. L. and Insogna, K. (2006) Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts. Bone 39, 1290-1301.
  48. Ory, S., Brazier, H., Pawlak, G. and Blangy, A. (2008) Rho GTPases in osteoclasts: orchestrators of podosome arrangement. Eur. J. Cell Biol. 87, 469-477.
  49. Chellaiah, M. A., Soga, N., Swanson, S., McAllister, S., Alvarez, U., Wang, D., Dowdy, S. F. and Hruska, K. A. (2000) Rho-A is critical for osteoclast podosome organization, motility, and bone resorption. J. Biol. Chem. 275, 11993-12002.
  50. Wang, Y., Lebowitz, D., Sun, C., Thang, H., Grynpas, M. D. and Glogauer, M. (2008) Identifying the relative contributions of Rac1 and Rac2 to osteoclastogenesis. J. Bone Miner Res. 23, 260-270.
  51. Etienne-Manneville, S. and Hall, A. (2002) Rho GTPases in cell biology. Nature 420, 629-635.
  52. Hornstein, I., Alcover, A. and Katzav, S. (2004) Vav proteins, masters of the world of cytoskeleton organization. Cell Signal 16, 1-11.
  53. Rossman, K. L., Der, C. J. and Sondek, J. (2005) GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat. Rev. Mol. Cell Biol. 6, 167-180.
  54. Faccio, R., Teitelbaum, S. L., Fujikawa, K., Chappel, J., Zallone, A., Tybulewicz, V. L., Ross, F. P. and Swat, W. (2005) Vav3 regulates osteoclast function and bone mass. Nat. Med. 11, 284-290.
  55. Patschan, D., Loddenkemper, K. and Buttgereit, F. (2001) Molecular mechanisms of glucocorticoid-induced osteoporosis. Bone 29, 498-505.
  56. Destaing, O., Saltel, F., Gilquin, B., Chabadel, A., Khochbin, S., Ory, S. and Jurdic, P. (2005) A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts. J. Cell Sci. 118, 2901-2911.
  57. Okumura, S., Mizoguchi, T., Sato, N., Yamaki, M., Kobayashi, Y., Yamauchi, H., Ozawa, H., Udagawa, N. and Takahashi, N. (2006) Coordination of microtubules and the actin cytoskeleton is important in osteoclast function, but calcitonin disrupts sealing zones without affecting microtubule networks. Bone 39, 684-693.

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