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Dexamethsone Suppresses Bone Formation via the Osteoclast

  • Hyun-Ju Kim
  • Haibo Zhao
  • Hideki Kitaura
  • Sandip Bhattacharyya
  • Judson A. Brewer
  • Louis J. Muglia
  • F. Patrick Ross
  • Steven L. Teitelbaum
Part of the Advances in Experimental Medicine and Biology book series (volume 602)

Glucocorticoids are central to treating inflammatory and immune disorders. These steroids, however, profoundly impact the skeleton, particularly when administered for prolonged periods. In fact, high-dose glucocorticoid therapy is almost universally associated with bone loss, prompting among the most common forms of crippling osteoporosis. Despite the frequency and severity of glucocorticoid-induced osteoporosis, its treatment is less than satisfactory, suggesting that its pathogenesis is incompletely understood.

Net bone mass represents the relative activities of osteoblasts and osteoclasts and there is little question that glucocorticoids suppress the bone-forming cells, in vivo, via a process involving accelerated apoptosis (Weinstein 2001; Weinstein, Jilka, Parfitt, et al. 1998). Surprisingly, however, addition of glucocorticoids to cultures of osteoprogenitor cells actually increases their capacity to form mineralized bone nodules (Aubin 1999; Purpura, Aubin, and Zandstra 2004). This paradox raises the possibility that glucocorticoid suppression of bone formation, in vivo, reflects, at least in part, the steroid’s targeting intermediary cells, which in turn inhibit the osteoblast.

Bone remodeling is an ever-occuring event in mammals which is characterized by tethering of osteoclast and osteoblast function. The process is initiated by osteoclasts (OCs) resorbing a packet of bone, which in turn leads to osteoblasts being recruited to the site of resorption. This process establishes that osteoclastic bone resorption, in some manner, promotes osteoblastic bone formation at the same location. Consequently, pathologically or pharmacologically inhibited resorption eventuates in arrested osteoblast activity.

Keywords

Bone Resorption Glucocorticoid Receptor Osteoprogenitor Cell Actin Ring Osteoblastic Bone Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 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.CrossRefPubMedGoogle Scholar
  2. Chellaiah, M.A., N. Soga, S. Swanson, S. McAllister, U. Alvarez, D. Wang, S.F. Dowdy, and K.A. Hruska. 2000. Rho-A is critical for osteoclast podosome organization, motility, and bone resorption. J Biol Chem 275: 11993–12002.CrossRefPubMedGoogle Scholar
  3. Dempster, D.W. 1989. Bone histomorphometry in glucocorticoid-induced osteoporosis. J Bone Miner Res 4: 137–141.CrossRefPubMedGoogle Scholar
  4. Faccio, R., S.L. Teitelbaum, K. Fujikawa, J.C. Chappel, A. Zallone, V.L. Tybulewicz, F.P. Ross, and W. Swat, 2005. Vav3 regulates osteoclast function and bone mass. Nat Med 11: 284–290.CrossRefPubMedGoogle Scholar
  5. Hirayama, T., A. Sabokbar, and N.A. Athanasou, 2002. Effect of corticosteroids on human osteoclast formation and activity. J Endocrinol 175: 155–163.CrossRefPubMedGoogle Scholar
  6. Hofbauer, L.C., F. Gori, B.L. Riggs, D.L. Lacey, C.R. Dunstan, T.C. Spelsberg, and S. Khosla, 1999. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinol 140: 4382–4389.CrossRefGoogle Scholar
  7. Kim, H.-J., H. Zhao, H. Kitaura, S. Bhattacharyya, J.A. Brewer, L.J. Muglia, F.P. Ross, and S.L. Teitelbaum. 2006. Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest 116: 2152–2160.CrossRefPubMedGoogle Scholar
  8. Korhonen, M., H. Zhao, R. Faccio, F.P. Ross, T.M. Hopkins, J.A. Cancelas, S.L. Teitelbaum, and D.A. Williams. 2005. Rac1 and Rac2 GTPases play distinct roles and are essential for full osteoclast differentiation. ASH Annual Meeting Abstracts 106: 67.Google Scholar
  9. Manolagas, S.C., and R.S. Weinstein. 1999. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Miner Res 14: 1061–1066.CrossRefPubMedGoogle Scholar
  10. Prummel, M.F., W.M. Wiersinga, P. Lips, G.T. Sanders, and H.P. Sauerwein. 1991. The course of biochemical parameters of bone turnover during treatment with corticosteroids. J Clin Endocrinol Metab 72: 382–386.CrossRefPubMedGoogle Scholar
  11. Purpura, K.A., J.E. Aubin, and P.W. Zandstra. 2004. Sustained in vitro expansion of bone progenitors is cell density dependent. Stem Cells 22: 39–50.CrossRefPubMedGoogle Scholar
  12. Rickard, D.J., T.A. Sullivan, B.J. Shenker, P.S. Leboy, and I. Kazhdan. 1994. Induction of rapid osteoblast differentiation in rat bone marrow stromal cell cultures by dexamethasone and BMP-2. Dev Biol 161: 218–228.CrossRefPubMedGoogle Scholar
  13. Rubin, J., D.M. Biskobing, L. Jadhav, D. Fan, M.S. Nanes, S. Perkins, and X. Fan. 1998. Dexamethasone promotes expression of membrane-bound macrophage colony-stimulating factor in murine osteoblast-like cells. Endocrinol 139: 1006–1012.CrossRefGoogle Scholar
  14. Teitelbaum, S.L. 2000. Bone resorption by osteoclasts. Science 289: 1504–1508.CrossRefPubMedGoogle Scholar
  15. Weinstein, R.S. 2001. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord 2: 65–73.CrossRefPubMedGoogle Scholar
  16. Weinstein, R.S., R.L. Jilka, A.M. Parfitt, and S.C. Manolagas. 1998. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. J Clin Invest 102: 274–282.CrossRefPubMedGoogle Scholar
  17. Weinstein, R.S., J.-R. Chen, C.C. Powers, S.A. Stewart, R.D. Landes, T. Bellido, R.L. Jilka, A.M. Parfitt, and S.C. Manolagas. 2002. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 109: 1041–1048.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Hyun-Ju Kim
    • 1
  • Haibo Zhao
    • 1
  • Hideki Kitaura
    • 1
  • Sandip Bhattacharyya
    • 2
  • Judson A. Brewer
    • 2
  • Louis J. Muglia
    • 1
  • F. Patrick Ross
    • 1
  • Steven L. Teitelbaum
    • 1
  1. 1.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA
  2. 2.Department of PediatricsWashington University School of MedicineSt. LouisUSA

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