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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]
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“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
“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
“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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“It has been reported [30] that continuous GC administration with slow release pellets for 27 days (a period equivalent in the mouse to *3–4 years in humans) decreases the number of OB and OC progenitors, decreases OB and OC surface, and increases OB and osteocyte apoptosis.”
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Duan, L., Zuo, J., Zhang, F., Li, B., Xu, Z., Zhang, H., Yang, B., Song, W., & Jiang, J. (2020) · International Journal of Nanomedicine · doi:10.2147/ijn.s244453 · Cited by 35
Kubo, Y., Drescher, W., Fragoulis, A., Tohidnezhad, M., Jahr, H., Gatz, M., Driessen, A., Eschweiler, J., Tingart, M., Wruck, C. J., et al. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8163 · Cited by 35
“Several studies have demonstrated corticosteroid-induced osteoblast or osteocyte dysfunction under in vitro conditions (166, 177, 184, 200).”
Hauser, B., Alonso, N., & Riches, P. L. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10071403 · Cited by 36
“There is a pathophysiological rationale for using anabolic treatment in GIOP as glucocorticoid treatment decreases proliferation of osteoblast precursors and stimulates osteoblast and osteocyte apoptosis, which together leads to a rapid reduction of bone formation [47,48].”
BackgroundMolecular Aspects of Bone Remodeling
Alma, Y., Valdés‐Flores, M., Orozco, L., & Velzquez-Cruz, R. (2013) · InTech eBooks · doi:10.5772/54905 · Cited by 42
“In adult bone, functional glucocorticoid receptors are found in pre-osteoblast/ stromal cells, osteoblasts (the cells that produce bone matrix), but not in osteoclasts [99].”
BackgroundPost-renal transplantation hypophosphatemia
Sakhaee, K. (2009) · Pediatric Nephrology · doi:10.1007/s00467-009-1252-4 · Cited by 35
Ileum resection is the most predictive factor for osteoporosis in patients with Crohn’s disease
van Hogezand, R. A., Bänffer, D., Zwinderman, A. H., McCloskey, E. V., Griffioen, G. G., & Hamdy, N. A. T. (2006) · Osteoporosis International · doi:10.1007/s00198-005-0016-7 · Cited by 35
“The relationship between long-term use of glucocorticoids and increased risk for osteoporosis and fractures is well established [10–19].”
BackgroundOsteoporosis in Systemic Lupus Erythematosus Mechanisms
Lee, C., & Ramsey‐Goldman, R. (2005) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2005.01.004 · Cited by 35
“Glucocorticoids can inhibit osteoblastogenesis and promote apoptosis of osteoblasts and osteocytes, key cells in bone formation [55].”
BackgroundSwolin‐Eide, D., Dahlgren, J., Nilsson, C., Wikland, K. A., Holmäng, A. B., & Ohlsson, C. (2002) · Journal of Endocrinology · doi:10.1677/joe.0.1740411 · Cited by 35
“Increasing evidence suggests that a mechanism for glucocorticoidinduced bone diseases arises from changes in osteoblast and osteocyte numbers due to apoptosis of these cells (Hughes & Boyce 1997, Weinstein et al. 1998, Weinstein & Manolagas 2000).”
BackgroundBone histology in steroid-treated children with non-azotemic nephrotic syndrome
Jofe, M. H., Salusky, I. B., Freundlich, M., & Goodman, W. G. (2004) · Pediatric Nephrology · doi:10.1007/s00467-003-1378-8 · Cited by 35
“The decrease in cell number is secondary to a decrease in osteoblastogenesis and an increase in the apoptosis of mature osteoblasts [33, 34].”
BackgroundInfluentialLegrand, É., Audran, M., Guggenbuhl, P., Levasseur, R., Chalès, G., Baslé, M. F., & Chappard, D. (2007) · Microscopy Research and Technique · doi:10.1002/jemt.20501 · Cited by 35
“Corticosteroids are known to depress bone formation by a direct effect on osteoblasts and by promoting apoptosis of osteocytes and osteoblasts (Weinstein et al., 1998; Weinstein and Manolagas, 2005).”
BackgroundGlucocorticoid-Induced Osteoporosis
Compston, J. E. (2003) · Hormone Research in Paediatrics · doi:10.1159/000074506 · Cited by 35
“Recently, the role of apoptosis in mediating glucocorticoid-induced bone loss has been emphasized, with reduced lifespan of osteoblasts and osteocytes and prolongation of the lifespan of osteoclasts [”
BackgroundSong, M., Zhao, D., Wei, S., Liu, C., Liu, Y., Wang, B., Zhao, W., Yang, K., Yong, Y., & Wu, H. K. (2014) · Bioelectromagnetics · doi:10.1002/bem.21867 · Cited by 34
“…the production of both and increasing the apoptosis of osteoblasts [Weinstein et al., 2002; Rauch et al., 2010]; induction of osteocytes apoptosis [Weinstein et al., 1998; O’Brien et al., 2004]; inhibition of BMSCs proliferation; and induction of BMSCs adipogenic differentiation while inhibiting…”
BackgroundSvendsen, P., Shekhrajka, N., Nielsen, K. L., Vestergaard, P., Thunbo, M. Ø., Vistisen, A. K., Munksgaard, P. S., Severinsen, M. T., Jensen, P., Johnsen, H. E., et al. (2016) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2016.1233543 · Cited by 32
“clasts[25] Finally, glucocorticoids interact directly with”
Webster, J. M., Fenton, C. G., LANGEN, R. C. J., & Hardy, R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225768 · Cited by 36
“The mechanism that underpins this appears to be primarily mediated by a substantial inhibition of osteoblastic bone formation [66].”
BackgroundPierce, J. L., Sharma, A. K., Roberts, R. L., Yu, K., Irsik, D. L., Choudhary, V., Dorn, J., Bensreti, H., Benson, R. D., Kaiser, H., et al. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4468 · Cited by 34
“, with Cushing’s syndrome) can compromise bone mass by inhibiting osteoblast differentiation and inducing osteoblast and osteocyte apoptosis.((29-31)) Additionally, exogenous glucocorticoid treatments for chronic inflammatory diseases contribute to the development of a secondary form of osteoporosis, glucocorticoid-in…”
BackgroundFarley, J. R., & Stilt-Coffing, B. (2001) · Calcified Tissue International · doi:10.1007/bf02685002 · Cited by 34
“Several recent studies have assessed the latter possibility [6, 40-45] and the related hypothesis that mechanical loading inhibits apoptosis in osteocytes [46].”
BackgroundRamli, E. S. M., Suhaimi, F., Asri, S. F. M., Ahmad, F., & Soelaiman, I. (2013) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-012-0413-x · Cited by 33
“Glucocorticoids inhibit osteoblastogenesis and promote apoptosis of osteoblasts and osteocytes which correlates with decrease in bone formation [18].”
BackgroundChiellini, C., Grenningloh, G., Cochet, O., Scheideler, M., Trajanoski, Z., Ailhaud, G. P., Dani, C., & Amri, E. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.06.121 · Cited by 34
Treating osteonecrosis with autologous bone marrow cells
Gangji, V., & Hauzeur, J. (2009) · Skeletal Radiology · doi:10.1007/s00256-009-0800-0 · Cited by 34
“Glucocorticoids inhibit osteoblastogenesis and promote osteoblast and osteocyte apoptosis [8, 9 ]. Apoptosis could disrupt the mechanosensory role of osteocytes and thus prevent the adaptation of bone to ischemia [9–11].”
BackgroundIyer, S. V., Han, L., Ambrogini, E., Yavropoulou, M. P., Fowlkes, J. L., Manolagas, S. C., & Almeida, M. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2934 · Cited by 34
“, Decatur, GA, USA) as previouslydescribed.((37,38)) Static anddynamichistomorphometry measurements of the cancellous bone were restricted to the secondary spongiosa.”
BackgroundSelf-citationReid, I. R. (1997) · Osteoporosis International · doi:10.1007/bf03194375 · Cited by 34
Olkku, A., Bodine, P. V. N., Linnala‐Kankkunen, A., & Mahonen, A. (2003) · Bone · doi:10.1016/j.bone.2003.09.010 · Cited by 34
“On the other hand, glucocorticoids have also been shown to induce apoptosis in mouse and rat osteoblastic cells in vivo [29,52].”
BackgroundDeletion of β1 Integrins from Cortical Osteocytes Reduces Load-Induced Bone Formation
Litzenberger, J. B., Tang, W. J., Castillo, A. B., & Jacobs, C. R. (2009) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-009-0068-4 · Cited by 33
Dexamethasone suppresses Smad3 pathway in osteoblastic cells
Iu, M.-F., Kaji, H., Sowa, H., Naito, J., Sugimoto, T., & Chihara, K. (2005) · Journal of Endocrinology · doi:10.1677/joe.1.05962 · Cited by 34
“GC decreases the number of osteoblasts and osteocytes by enhanced apoptosis as well as suppressed turnover of cell cycle (Weinstein et al. 1998, Smith et al. 2000, 2002).”
BackgroundSambrook, P. N., & Lane, N. E. (2001) · Best Practice & Research Clinical Rheumatology · doi:10.1053/berh.2001.0157 · Cited by 35
STEROID–INDUCED OSTEOPOROSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS
Cunnane, G., & Lane, N. E. (2000) · Rheumatic Disease Clinics of North America · doi:10.1016/s0889-857x(05)70140-x · Cited by 33
Moriishi, T., Fukuyama, R., Miyazaki, T., Furuichi, T., Ito, M., & Komori, T. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2808 · Cited by 33
Bensreti, H., Alhamad, D. W., Marrero‐Gonzalez, A. R., Pizarro-Mondesir, M., Bollag, W. B., Isales, C. M., & McGee‐Lawrence, M. E. (2022) · Current Osteoporosis Reports · doi:10.1007/s11914-022-00772-5 · Cited by 33
Goldberg, D., Dodds, K., Avitabile, C. M., Glatz, A. C., Brodsky, J. L., Semeao, E. J., Rand, E. B., Mancilla, E. E., & Rychik, J. R. (2012) · Pediatric Cardiology · doi:10.1007/s00246-012-0290-z · Cited by 33
“The mechanism appears to be via decreased osteoblastic activity and increased osteocyte apoptosis [12, 21].”
BackgroundHuo, L., Wang, L., Yang, Z., Li, P., Geng, D., & Xu, Y. (2018) · Biology Open · doi:10.1242/bio.029405 · Cited by 33
Yang, L., Liu, S., Mu, S., Guo, R., Zhou, L., & Fu, Q. (2021) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2021/6623464 · Cited by 33
“Reduced osteoblast viability is the primary effect of excess GCs on bone metabolism, which can subsequently lead to a decrease in osteoblast numbers without affecting bone resorption [17].”
Backgroundl-Carnitine protects against apoptosis of murine MC3T3-E1 osteoblastic cells
Xie, H., Tang, S., Li, H., Luo, X., Yuan, L., Wang, D., & Liao, E.-Y. (2007) · Amino Acids · doi:10.1007/s00726-007-0598-9 · Cited by 33
“Studies in mice and humans, as well as in vitro experiments, strongly suggest that the deleterious effects of GCs on the skeleton are partially caused by proapop- totic effects on osteoblasts (Weinstein et al., 1998; Gohel et al., 1999; Canalis and Delany, 2002).”
BackgroundVedi, S., Elkin, S., & Compston, J. E. (2005) · Calcified Tissue International · doi:10.1007/s00223-004-0205-y · Cited by 33
“Direct effects on osteoblastogenesis, together with increased apoptosis of osteoblasts and osteocytes, are believed to be mainly responsible for reduced bone formation [17, 18].”
BackgroundRaheja, L. F., Genetos, D. C., & Yellowley, C. E. (2009) · Cells Tissues Organs · doi:10.1159/000235679 · Cited by 33
“…in Low Oxygen Cells Tissues Organs 2010;191:175–184 179 Alkaline Phosphatase Activity and Calcium Deposition Increase with Increasing Oxygen Tension and Days in Culture ALP, a cell surface enzyme involved in skeletal mineralization, is a marker of osteoblastic differentiation [Whyte, 2002].”
BackgroundBiomarkers of Bone Turnover after a Short Period of Steroid Therapy in Elderly Men
Paglia, F., Dionisi, S., Geronimo, S. D., Rosso, R., Romagnoli, E., Raejentroph, N., Ragno, A., Celi, M., Pepe, J., D'Erasmo, E., et al. (2001) · Clinical Chemistry · doi:10.1093/clinchem/47.7.1314 · Cited by 32
“The effect of glucocorticoids on bone consists of reduced bone formation with decreased wall thickness of the trabeculae, a strong indication of the decreased output of osteoblasts (7, 8).”
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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