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Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone.
Open accessAbstract
Glucocorticoid-induced bone disease is characterized by decreased bone formation and in situ death of isolated segments of bone (osteonecrosis) suggesting that glucocorticoid excess, the third most common cause of osteoporosis, may affect the birth or death rate of bone cells, thus reducing their numbers. To test this hypothesis, we administered prednisolone to 7-mo-old mice for 27 d and found decreased bone density, serum osteocalcin, and cancellous bone area along with trabecular narrowing. These changes were accompanied by diminished bone formation and turnover, as determined by histomorphometric analysis of tetracycline-labeled vertebrae, and impaired osteoblastogenesis and osteoclastogenesis, as determined by ex vivo bone marrow cell cultures. In addition, the mice exhibited a threefold increase in osteoblast apoptosis in vertebrae and showed apoptosis in 28% of the osteocytes in metaphyseal cortical bone. As in mice, an increase in osteoblast and osteocyte apoptosis was documented in patients with glucocorticoid-induced osteoporosis. Decreased production of osteoclasts explains the reduction in bone turnover, whereas decreased production and apoptosis of osteoblasts would account for the decline in bone formation and trabecular width. Furthermore, accumulation of apoptotic osteocytes may contribute to osteonecrosis. These findings provide evidence that glucocorticoid-induced bone disease arises from changes in the numbers of bone cells.
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“A high level of glucocorticoid in smokers alters bone metabolism and decreases bone mass either directly by changing the osteoblast and osteoclast activities or indirectly by altering the gastrointestinal absorption and renal reabsorption of calcium [39–42].”
From The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms (2018) · cites this paper as [39]
Experimental — accuracy not yet measuredIn the citing paper
“In mice, BMD loss with prednisolone was associated with decreased osteocalcin and decreased bone formation, with no histological or biochemical evidence for increased bone resorption (251).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [251]
In the citing paper
“bone marrow harvested from mice treated with prednisolone showed reduced osteoclastogenic potential (251).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [251]
In the citing paper
“One important component of glucocorticoid biology that is lacking in most cell culture models is the marked depletion of osteoblast numbers in animals treated with glucocorticoids (251).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [251]
In the citing paper
“Bone marrow harvested from mice treated with prednisolone was shown to have markedly reduced osteoblastogenic capacity (251).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [251]
In the citing paper
“Glucocorticoids can also inhibit osteoblast differentiation (249 -251), osteoblast attachment to bone matrix (252), and osteoblast production of IGF-I (253).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [251]
In the citing paper
“The prednisolonerelated increase in bone volume in rats, confirmed in a study described immediately below (262), is not consistent with histological data from patients with glucocorticoid-induced osteoporosis (194) and is a recognized limitation of the model (251).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [251]
In the citing paper
“Glucocorticoids decrease BMD in rats (262, 263), mice (251), and minipigs (264).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [251]
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“Preclinical models have shown excess glucocorticoids that also affect bone formation and resorption processes by reducing osteoblast production and lifespan and prolonging the lifespan of osteoclasts [73].”
BackgroundPlotkin, L. I., Bivi, N., & Bellido, T. (2010) · Bone · doi:10.1016/j.bone.2010.08.011 · Cited by 81
“On the other hand, prednisolone increased osteoblast, and cancellous and cortical osteocyte apoptosis, as previously shown [3,6,27,28], and daily injections of either alendronate or IG9402 prevented this effect.”
Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis
Gu, G., Hentunen, T. A., Nars, M., Härkönen, P. L., & Väänänen, H. K. (2005) · APOPTOSIS · doi:10.1007/s10495-005-1893-0 · Cited by 78
Costa, P. F., Puga, A. M., Díaz-Gomez, L., Concheiro, A., Busch, D. H., & Alvarez-Lorenzo, C. (2015) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2015.10.055 · Cited by 78
Autophagy as a target for glucocorticoid-induced osteoporosis therapy
Shen, G., Ren, H. J., Shang, Q., Qiu, T., Yu, X., Zhang, Z., Huang, J., Zhao, W., Zhang, Y., Liang, D., et al. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2776-1 · Cited by 76
Energy Metabolism During Osteogenic Differentiation: The Role of Akt
Smith, C. O., & Eliseev, R. A. (2020) · Stem Cells and Development · doi:10.1089/scd.2020.0141 · Cited by 77
“Complete remodeling of bone in mice occurs in 2 weeks, whereas humans require up to 9 months [46,51,52].”
BackgroundSkeletal unloading induces osteoblast apoptosis and targets α5β1-PI3K-Bcl-2 signaling in rat bone
Dufour, C., Holy, X., & Marie, P. J. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.10.021 · Cited by 75
Skeletal morbidity in inflammatory bowel disease
van Hogezand, R. A., & Hamdy, N. A. T. (2006) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365520600664276 · Cited by 77
“[48] Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC.”
BackgroundBruedigam, C., Eijken, M., Koedam, M., van de Peppel, J., Drabek, K., Chiba, H., & van Leeuwen, J. P. T. M. (2010) · Stem Cells · doi:10.1002/stem.405 · Cited by 77
Gandhi, M. K., Lekamwasam, S., Inman, I., Kaptoge, S., Sizer, L., Love, S., Bearcroft, P. W. P., Milligan, T. P., Price, C. P., Marcus, R. E., et al. (2003) · British Journal of Haematology · doi:10.1046/j.1365-2141.2003.04303.x · Cited by 77
“…D deficiency, immobilization, graft-versus-host disease (GVHD) and its treatment (Katz & Epstein, 1992; Laan et al, 1993; Carlson et al, 1994; Weinstein et al, 1998), malignancy-related mechanisms, ovarian insufficiency in women, and altered cellular or cytokine-mediated bone marrow function…”
BackgroundTang, Y., Xie, H., Chen, J., Geng, L., Chen, H., Li, X., Hou, Y., Lu, L., Shi, S., Zeng, X., et al. (2012) · Stem Cells and Development · doi:10.1089/scd.2012.0226 · Cited by 78
“It is reported that GC alters bone metabolism at the cellular and molecular levels not only by increasing osteoclastic action [55] but also by inhibiting osteoblastic growth and differentiation [56,57].”
Long-Term Persistence of Low Bone Density in Orthotopic Liver Transplantation
Giannini, S., Nobile, M., Ciuffreda, M., Iemmolo, R. M., Carbonare, L. D., Minicuci, N., Casagrande, F., Destro, C., Gerunda, G. E., Sartori, L., et al. (2000) · Osteoporosis International · doi:10.1007/s001980070109 · Cited by 77
“Corticosteroids affect osteoblast function in several ways [12, 13 ].”
BackgroundApoptosis in the Osteonecrosis of the Femoral Head
Youm, Y.-S., Lee, S., & Lee, S.-H. (2010) · Clinics in Orthopedic Surgery · doi:10.4055/cios.2010.2.4.250 · Cited by 76
Glucocorticoid-induced osteoporosis: a review on pathophysiology and treatment options.
de Nijs, R. N. J. (2008) · PubMed · Cited by 74
The skeleton as a unique environment for breast cancer cells
Mastro, A. M., Gay, C. V., & Welch, D. R. (2003) · Clinical & Experimental Metastasis · doi:10.1023/a:1022995403081 · Cited by 76
“In addition, glucocorticoids may increase osteoblast and osteocyte apoptosis [80].”
BackgroundFerrari, P. (2003) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/s1521-690x(03)00053-8 · Cited by 76
Inhibition of osteoblast apoptosis by thrombin
Pagel, C. N., de Niese, M. R., Abraham, L. A., Chinni, C., Song, S., Pike, R. N., & Mackie, E. J. (2003) · Bone · doi:10.1016/s8756-3282(03)00209-6 · Cited by 75
“Osteoblast apoptosis is increased in association with inflammation-mediated osteoporosis [1] and glucocorticoid-induced osteoporosis [2], and agents effective in managing the latter condition, such as bisphosphonates and calcitonin, inhibit glucocorticoid-induced osteoblast apoptosis [3].”
BackgroundSubramanian, G., Cohen, H. V., & Quek, S. Y. P. (2011) · Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology · doi:10.1016/j.tripleo.2011.04.020 · Cited by 76
Pineau, C. A., Urowitz, M. B., Fortin, P. R., Ibanez, D., & Gladman, D. D. (2004) · Lupus · doi:10.1191/0961203303lu1036oa · Cited by 74
Pasqualetti, S., Congiu, T., Banfi, G., & Mariotti, M. (2015) · International Journal of Experimental Pathology · doi:10.1111/iep.12106 · Cited by 74
“Some data reported that osteoclastogenesis is increased in mice after 7 days of treatment with prednisolone, whereas it was decreased by 60% after 21 days (Weinstein et al. 1998).”
BackgroundSteroids and osteoporosis: the quest for mechanisms
Manolagas, S. C. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68062 · Cited by 74
“In two papers published in JCI two months apart in 1998, we demonstrated that both estrogens and glucocorticoids restrain osteoblastogenesis and that gluco-corticoids shorten the lifespan of mature osteoblasts and osteocytes by stimulating apoptosis (11, 12).”
Self-citationEffect of glucocorticoids on bone density
Rehman, Q., & Lane, N. E. (2003) · Medical and Pediatric Oncology · doi:10.1002/mpo.10339 · Cited by 74
Karaplis, A. C. (2002) · Elsevier eBooks · doi:10.1016/b978-012098652-1.50105-0 · Cited by 76
Therapy Insight: osteoporosis and osteonecrosis in systemic lupus erythematosus
Lane, N. E. (2006) · Nature Clinical Practice Rheumatology · doi:10.1038/ncprheum0298 · Cited by 72
IL-6 receptor expression and IL-6 effects change during osteoblast differentiation
Li, Y., Bäckesjö, C., Haldosén, L.-A., & Lindgren, U. (2008) · Cytokine · doi:10.1016/j.cyto.2008.05.007 · Cited by 75
Risk factors of vertebral fractures in women with systemic lupus erythematosus
Pinto, C. M., García‐Carrasco, M., Sandoval-Cruz, H., Muñóz‐Guarneros, M., Escarcega, R. O., Jiménez-Hernández, M., Munguía‐Realpozo, P., Sandoval-Cruz, M., Delezé-Hinojosa, M., López‐Colombo, A., et al. (2009) · Clinical Rheumatology · doi:10.1007/s10067-009-1105-3 · Cited by 72
“It has been demonstrated that chronic CTS administration to mice and humans increases the prevalence of osteocyte and osteoblast apoptosis and an osteocyte accumulation exists [23].”
BackgroundGlucocorticoids 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
Effects of prednisolone on skeletal muscle contractility in mdx mice
Baltgalvis, K. A., Call, J. A., Nikas, J. B., & Lowe, D. A. (2009) · Muscle & Nerve · doi:10.1002/mus.21327 · Cited by 75
THE 2003 MARSHALL R. URIST AWARD PAPER: Genetic Background of Osteonecrosis
Zalavras, C. G., Vartholomatos, G., Dokou, E., & Malizos, Κ. Ν. (2004) · Clinical Orthopaedics and Related Research · doi:10.1097/01.blo.0000127921.13253.e3 · Cited by 72
“Moreover, the coexistence of pathogenetic mechanisms other than intravascular coagulation should be considered, such as induction of osteocyte apoptosis.(25,26) Factor V Leiden, an established genetic risk factor for venous thrombosis, is associated with ON of the femoral head.”
BackgroundBone disease after renal transplantation
Kunzendorf, U., Krämer, B. K., Arns, W., Braun, J., Grossmann, J., Pietruck, F., Schmidt-Gayk, H., Schwarz, A., Ziegler, E., Sperschneider, H., et al. (2007) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfm816 · Cited by 72
“(1) Reduced bone formation: as in a number of other cell types, steroids induce apoptosis in osteoblasts and osteocytes and inhibit osteoblastogenesis by blocking the division and differentiation of osteoblasts [35].”
Inflammatory Diseases and Growth: Effects on the GH–IGF Axis and on Growth Plate
Cirillo, F., Lazzeroni, P., Sartori, C., & Street, M. E. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18091878 · Cited by 72
“Glucocorticoids act directly on osteoblasts, decreasing their proliferation and the consequent production of specific proteins as osteocalcin, a bone specific alkaline phosphatase [145,146].”
O’Brien, C. A., Jilka, R. L., Fu, Q., Stewart, S. A., Weinstein, R. S., & Manolagas, S. C. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00029.2005 · Cited by 71
“The first through the fourth lumbar vertebrae were fixed and embedded undecalcified in methyl methacrylate as previously described (55).”
MethodSelf-citationFeng, R., Li, F., Yuan, Z., Wang, D., Wang, F., Tan, B., Han, S., Li, T., Li, D., & Han, Y. (2013) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-013-9533-8 · 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
“(13) and inhibition of osteoblast proliferation and”
Tufvesson, E., & Westergren‐Thorsson, G. (2000) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(20000501)77:2 · Cited by 65
Gafni, R. I., McCarthy, E. F., Hatcher, T., Meyers, J. L., Inoue, N., Reddy, C. C., Weise, M., Barnes, K. M., Abad, V., & Baron, J. (2002) · The FASEB Journal · doi:10.1096/fj.01-0640fje · Cited by 71
“In glucocorticoid-treated animals, the cortical width was decreased while the marrow diameter was unaffected, indicating that the major effect of glucocorticoid excess is not the stimulation of bone resorption but rather the inhibition of bone formation, as has been previously described (18).”
ResultChen, C., Du, W., Rao, S., Tan, Y., Hu, X., Luo, M., Ou, Q., Wu, P., Qing, L., Cao, Z., et al. (2020) · Acta Biomaterialia · doi:10.1016/j.actbio.2020.05.020 · Cited by 71
Talamo, G., Angtuaco, E., Walker, R. C., Li, D., Miceli, M. H., Zangari, M., Tricot, G. J. K., Barlogie, B., & Anaissie, E. J. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.11.676 · Cited by 70
HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway
Xu, W., Zheng, H., Yang, R., Jiang, L., & Jiang, S. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00922 · Cited by 69
“of osteoblasts are involved in GC-induced osteogenic inhibition in bone cells (3, 7).”
BackgroundPost-renal transplantation hypophosphatemia: a review and novel insights
Ghanekar, H., Welch, B. J., Moe, O. W., & Sakhaee, K. (2006) · Current Opinion in Nephrology & Hypertension · doi:10.1097/01.mnh.0000203187.49890.cc · Cited by 69
Glucocorticoid-induced osteoporosis
Reid, I. R. (2000) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1053/beem.2000.0074 · Cited by 71
“demise of both osteoblasts and osteocytes, further contributing to reduced bone formation.(5,6) These eects are seen in both animal and human histomorphometric”
BackgroundSecondary osteoporosis: Pathophysiology & diagnosis
Emkey, G. R., & Epstein, S. (2014) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2014.07.002 · Cited by 71
“Glucocorticoids cause decreased production of osteoblast precursors and increased apoptosis of mature osteoblasts [6,7].”
Background
Metadata
- Authors
- Weinstein, R. S., Jilka, R. L., Parfitt, A. M., & Manolagas, S. C.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1998-07-15
- Volume
- 102
- Issue
- 2
- Pages
- 274-282
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508885
- OpenAlex
- W2002315967
- Cited by
- 1,753
- References
- 56
- Citations by year
- 2026: 25 · 2025: 35 · 2024: 44 · 2023: 63 · 2022: 55 · 2021: 69 · 2020: 65 · 2019: 60 · 2018: 59 · 2017: 63 · 2016: 72 · 2015: 59 · 2014: 77 · 2013: 70 · 2012: 74
- FWCI
- 15.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health (5r01ar043003-05)
- National Institute on Aging (P01 AG-13918, P01AG013918)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR43003)
- 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
- glucocorticoid-induced osteoporosis, osteoblastogenesis, osteoblast apoptosis, osteocyte apoptosis, prednisolone, avascular necrosis, bone formation, bone turnover, osteoclastogenesis, trabecular bone, bone mineral density, osteocalcin
- MeSH terms
- Adult, Animals, Bone and Bones, Bone Marrow Cells, Bone Resorption, Cells, Cultured, Female, Glucocorticoids, Humans, Male, Osteoblasts, Osteocytes, Osteoporosis, Prednisolone, Spine, Bone Density, Apoptosis, Mice
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