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Glucocorticoids suppress bone formation via the osteoclast.
Open accessAbstract
The pathogenesis of glucocorticoid-induced (GC-induced) bone loss is unclear. For example, osteoblast apoptosis is enhanced by GCs in vivo, but they stimulate bone formation in vitro. This conundrum suggests that an intermediary cell transmits a component of the bone-suppressive effects of GCs to osteoblasts in the intact animal. Bone remodeling is characterized by tethering of the activities of osteoclasts and osteoblasts. Hence, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To define the direct impact of GCs on bone-resorptive cells, we compared the effects of dexamethasone (DEX) on WT osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells (GRoc-/- mice). While the steroid prolonged longevity of osteoclasts, their bone-degrading capacity was suppressed. The inhibitory effect of DEX on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M-CSF. DEX specifically arrested M-CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances GRoc-/- mice were spared the impact of DEX on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast-suppressive effect of DEX, GRoc-/- mice are protected from the steroid's inhibition of bone formation.
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“DEX was recently shown to prolong the lifespan of osteoclasts, while decreasing their individual capacity to degrade bone (257).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [257]
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Kim, C. W., Yun, Y.-P., Lee, H. J., Hwang, Y., Kwon, I. K., & Lee, S. C. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.06.016 · Cited by 76
The nuclear receptor superfamily of steroid hormones and vitamin D gene regulation
Margolis, R., & Christakos, S. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05227.x · Cited by 77
Extrinsic Mechanisms Involved in Age-Related Defective Bone Formation
Marie, P. J., & Kassem, M. S. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2113 · Cited by 78
Hypercortisolemia and Infection
Fareau, G. G., & Vassilopoulou‐Sellin, R. (2007) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2007.06.001 · Cited by 75
Pasqualetti, S., Congiu, T., Banfi, G., & Mariotti, M. (2015) · International Journal of Experimental Pathology · doi:10.1111/iep.12106 · Cited by 74
“An additional study in mice lacking glucocorticoid receptor by osteoclasts demonstrated that glucocorticoids prolonged the life span of osteoclasts (Kim et al. 2006).”
BackgroundPhosphate Regulates Osteopontin Gene Transcription
Fatherazi, S., Matsa-Dunn, D., Foster, B. L., Rutherford, R. B., Somerman, M. J., & Presland, R. B. (2009) · Journal of Dental Research · doi:10.1177/0022034508328072 · Cited by 73
“Clinically, the use of glucocorticoids to treat inflammatory diseases often leads to osteoporosis, due to the inhibition of osteoclast-mediated bone resorption and arrested bone formation (Kim et al., 2006).”
BackgroundAcute Effects of Glucocorticoids on Serum Markers of Osteoclasts, Osteoblasts, and Osteocytes
Maresova, K. B., Pavelká, K., & Stepan, J. J. (2012) · Calcified Tissue International · doi:10.1007/s00223-012-9684-4 · Cited by 73
“Supraphysiological concentrations of GC induce an early upregulation of genes associated with osteoclast cytoskeletal reorganization and organic bone matrix degradation [5] and stimulate bone resorption by promoting osteoclast survival and activity [6, 7].”
Glucocorticoids and the Osteoclast
KIM, H., Zhao, H., Kitaura, H., Bhattacharyya, S., Brewer, J. A., Muglia, L. J., Ross, F. P., & Teitelbaum, S. L. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1402.057 · Cited by 71
Self-citationRole of Plasminogen Activator Inhibitor-1 in Glucocorticoid-Induced Diabetes and Osteopenia in Mice
Tamura, Y., Kawao, N., Yano, M., Okada, K., Okumoto, K., Chiba, Y., Matsuo, O., & Kaji, H. (2014) · Diabetes · doi:10.2337/db14-1192 · Cited by 70
“Furthermore, GC suppresses the formation of osteoclast precursors (41,42).”
BackgroundAnastasilakis, A. D., Tsourdi, E., Makras, P., Polyzos, S. A., Meier, C., McCloskey, E. V., Pepe, J., & Zillikens, M. C. (2019) · Bone · doi:10.1016/j.bone.2019.07.006 · Cited by 71
Rauch, A., Gossye, V., Bracke, D., Gevaert, E., Jacques, P., Beneden, K. V., Vandooren, B., Rauner, M., Hofbauer, L. C., Haegeman, G., et al. (2011) · The FASEB Journal · doi:10.1096/fj.10-173393 · Cited by 71
“In the initial phase of pharmacological GC exposure, it is assumed that osteoclastogenesis rises by disturbing the RANKL/OPG ratio or, more specifically, via RANKL induction and transrepression of OPG expression (38) and by a prolonged osteoclast survival (11, 39, 40).”
BackgroundCommensal-Epithelial Signaling Mediated via Formyl Peptide Receptors
Wentworth, C. C., Jones, R. M., Kwon, Y. M., Nusrat, A., & Neish, A. S. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.100529 · Cited by 73
c-Src Links a RANK/αvβ3 Integrin Complex to the Osteoclast Cytoskeleton
Izawa, T., Zou, W., Chappel, J. C., Ashley, J. W., Feng, X., & Teitelbaum, S. L. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00077-12 · Cited by 72
“The cells were then incubated, cytokine free, at 37°C for 30 min, after which they were exposed to RANKL or PBS for 15, 30, 60, or 120 min (13).”
MethodDissection of platelet and myeloid cell defects by conditional targeting of the β3‐integrin subunit
Morgan, E. A., Schneider, J. G., Baroni, T. E., Uluçkan, Ö., Heller, E., Hurchla, M. A., Deng, H., Floyd, D. H., Berdy, A., Prior, J. L., et al. (2009) · The FASEB Journal · doi:10.1096/fj.09-138420 · Cited by 68
“The LysM-Cre mice have been successfully used to obtain a tissue-specific gene deletion in OCs (37).”
MethodCorticosterone selectively targets endo-cortical surfaces by an osteoblast-dependent mechanism
Henneicke, H., Herrmann, M., Kalak, R., Brennan‐Speranza, T. C., Heinevetter, U., Bertollo, N., Day, R. E., Huscher, D., Buttgereit, F., Dunstan, C. R., et al. (2011) · Bone · doi:10.1016/j.bone.2011.06.013 · Cited by 67
“Even though a contribution of direct GC effects on osteoclasts cannotbe ruledout entirely [28], our results suggest thatGCinduced osteoclast activity and bone resorption are mediated via changes inosteoblast function.”
BackgroundGlucocorticoid receptor action in metabolic and neuronal function
Garabedian, M. J., Harris, C. A., & Jeanneteau, F. D. (2017) · F1000Research · doi:10.12688/f1000research.11375.1 · Cited by 69
Glucocorticoid-induced autophagy and apoptosis in bone
Wang, T., Liu, X., & He, C. (2020) · APOPTOSIS · doi:10.1007/s10495-020-01599-0 · Cited by 67
Wang, L., Singh, M. K., Bonewald, L. F., & Detamore, M. S. (2009) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.176 · Cited by 65
“However, the differentiation factors, including dexamethasone and 1α,25-dihydroxyvitamin D3, may inhibit cell proliferation (Walsh et al., 2001; Atmani et al., 2003; Chen, 2004; Kim et al., 2006) for both BMSCs and osteoblasts.”
BackgroundSiddappa, R., Fernandes, H., Liu, J., van Blitterswijk, C., & de Boer, J. (2007) · Current Stem Cell Research & Therapy · doi:10.2174/157488807781696267 · Cited by 66
Role of nutritional vitamin D in osteoporosis treatment
Hou, Y., Wu, C., Liao, M.-T., Shyu, J., Hung, C., Yen, T., Lu, C., & Lu, K. (2018) · Clinica Chimica Acta · doi:10.1016/j.cca.2018.05.035 · Cited by 65
Yang, P., Lv, S., Wang, Y., Peng, Y., Ye, Z.-X., Xia, Z., Ding, G.-X., Cao, X., & Crane, J. L. (2018) · Bone · doi:10.1016/j.bone.2018.05.025 · Cited by 60
“The direct effect of glucocorticoids on osteoclasts appear to contribute significantly to skeletal fragility [14, 15, 34].”
BackgroundCurrent Treatments and New Developments in the Management of Glucocorticoid-induced Osteoporosis
Raterman, H. G., Bultink, I. E. M., & Lems, W. F. (2019) · Drugs · doi:10.1007/s40265-019-01145-6 · Cited by 64
Okumura, A., Saito, T., Otani, I., Kojima, K., Yamada, Y., Ishida‐Okawara, A., Nakazato, K., Asano, M., KANAYAMA, K., Iwakura, Y., et al. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23215 · Cited by 63
Tsampalieros, A. K., Gupta, P., Denburg, M., Justine Shults, A., Zemel, B. S., Mostoufi‐Moab, S., Wetzsteon, R. J., Herskovitz, R. M., Whitehead, K., & Leonard, M. B. (2012) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1785 · Cited by 65
“GCs promote osteoclastogenesis and inhibit osteoclast apoptosis,((3)) but GCs also directly impair osteoclast adherence to bone and bone degradation, resulting in an eventual state of low bone turnover.((5)) In this study, we demonstrated that GC therapy was associated with declines in BSAP Z-scores but was not associ…”
BackgroundThe Role of Sclerostin in Bone Diseases
Vasiliadis, E. S., Evangelopoulos, D.-S., Kaspiris, A., Benetos, I. S., Vlachos, C., & Pneumaticos, S. G. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030806 · Cited by 62
“Thus, targeting sclerostin with an antisclerostin antibody could be beneficial for the treatment of glucocorticoid-induced osteoporosis [54].”
Background
Metadata
- Authors
- Kim, H.-J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Kim, H.-J.
- ORCID
- Kim, H.-J.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-08-01
- Volume
- 116
- Issue
- 8
- Pages
- 2152-2160
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1518793
- OpenAlex
- W2102680446
- Cited by
- 384
- References
- 47
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 7 · 2023: 11 · 2022: 16 · 2021: 23 · 2020: 22 · 2019: 21 · 2018: 21 · 2017: 9 · 2016: 17 · 2015: 25 · 2014: 18 · 2013: 12 · 2012: 25
- FWCI
- 11.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Institutes of Health (DK 056341, AR046523)
- National Institute of Allergy and Infectious Diseases (AI50655, R01AI050655, R21AI050655)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 056341, P30DK056341)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 048853, AR 046852, AR 032788, R01AR048812, AR 048812, R01AR032788, R37AR046523, AR046523, R01AR048853, R01AR046852, R01AR046523)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- glucocorticoids, glucocorticoid-induced osteoporosis, osteoclasts, bone formation, dexamethasone, glucocorticoid receptor, RhoA, Rac, Vav3, osteoclast precursors, bone remodeling, osteoblast apoptosis
- MeSH terms
- Animals, Bone Development, Bone Resorption, Cell Survival, Dexamethasone, Glucocorticoids, Osteoclasts, Receptors, Glucocorticoid, Mice, Knockout, Mice
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