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Osteoblast Programmed Cell Death (Apoptosis): Modulation by Growth Factors and Cytokines
Open accessAbstract
Once osteoblasts have completed their bone-forming function, they are either entrapped in bone matrix and become osteocytes or remain on the surface as lining cells. Nonetheless, 50–70% of the osteoblasts initially present at the remodeling site cannot be accounted for after enumeration of lining cells and osteocytes. We hypothesized that the missing osteoblasts die by apoptosis and that growth factors and cytokines produced in the bone microenvironment influence this process. We report that murine osteoblastic MC3T3-E1 cells underwent apoptosis following removal of serum, or addition of tumor necrosis factor (TNF), as indicated by terminal deoxynucleotidyl transferase–mediated dUTP-nick end labeling and DNA fragmentation studies. Transforming growth factor-β and interleukin-6 (IL-6)–type cytokines had antiapoptotic effects because they were able to counteract the effect of serum starvation or TNF. In addition, anti-Fas antibody stimulated apoptosis of human osteoblastic MG-63 cells and IL-6–type cytokines prevented these changes. The induction of apoptosis in MG-63 cells was associated with an increase in the ratio of the proapoptotic protein bax to the antiapoptotic protein bcl-2, and oncostatin M prevented this change. Examination of undecalcified sections of murine cancellous bone revealed the presence of apoptotic cells, identified as osteoblasts by their proximity to osteoid seams and their juxtaposition to cuboidal osteoblasts. Assuming an osteoblast life span of 300 h and a prevalence of apoptosis of 0.6%, we calculated that the fraction that undergo this process in vivo can indeed account for the missing osteoblasts. These findings establish that osteoblasts undergo apoptosis and strongly suggest that the process can be modulated by growth factors and cytokines produced in the bone microenvironment.
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“At this stage, the mature osteoblasts can undergo apoptosis or become osteocytes or bone lining cells [47, 48].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [48]
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BackgroundOSTEOIMMUNOLOGY: Interplay Between the Immune System and Bone Metabolism
Walsh, M. C., Kim, N., Kadono, Y., Rho, J., Lee, S. Y., Lorenzo, J., & Choi, Y. (2006) · Annual Review of Immunology · doi:10.1146/annurev.immunol.24.021605.090646 · Cited by 724
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Molecular and cellular mechanisms of the anabolic effect of intermittent PTH
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“In normal mice, about 1 in 150 osteoblasts are undergoing apoptosis at a given moment as determined by TUNEL in our original study [30].”
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“Apoptosis of osteoblasts is blocked by TGF- 1 through maintenance of survival during transdifferentiation into osteocytes (93, 126, 127).”
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“TNF is potently proapoptotic for osteoblasts (497), possibly through induction of the Fas-FasL system (498).”
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“Based on our studies indicating that the majority of osteoblasts die by apoptosis (Jilka et al., 1998b), we have turned our attention to the effects of estrogens as well as androgens on osteoblast and osteocyte apoptosis.”
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Modeling the interactions between osteoblast and osteoclast activities in bone remodeling
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“Eventually, osteoblasts either die or transform to either lining cells or osteocytes (Jilka et al., 1998).”
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“Among these are the interleukins IL-6 and IL-11 [Jilka et al., 1998; Manolagas, 1998; Lian et al., 1999].”
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“This system allows for sensitive and specific staining of the high concentrations of 39-OH ends that accumulate with DNA fragmentation due to apoptosis (7, 12).”
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Manolagas, S. C., & Weinstein, R. S. (1999) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.1999.14.7.1061 · Cited by 382
“The majority of osteoblasts (50–70%) also die by apoptosis once they have completed their boneforming tasks.((11)) The remaining osteoblasts have one of two alternative fates: they can become elongated “lining cells” that cover the newly formed bone surface; or they can be entrapped in the mineralized matrix to become…”
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Self-citationInjurious Mechanical Compression of Bovine Articular Cartilage Induces Chondrocyte Apoptosis
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“中更为突出,暗示诱导细胞凋亡造成的更新骨形成 有可能与巨噬细胞活性相关([75])。 成骨细胞的详细组织学研究显示约15%的成骨 细胞发育为骨细胞,30%发育为骨衬细胞([76]),剩余的 40%~70%下落不明([76,77])。据推测这些细胞进入凋亡程 序并随后被清除。因此,大多数成骨细胞的命运是”
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“A major fraction of osteoblasts at bone remodeling sites cannot be accounted for and probably undergo apoptosis (Jilka et al., 1998) and the anabolic effect of PTH is due to its antiapoptotic effect on osteoblasts (Jilka et al., 1999).”
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“It has been shown that PTH can prevent apoptosis of osteocytes (and osteoblasts) and that this mechanism may contribute to the anabolic action of intermittently administered PTH (Jilka et al. 1998, 1999).”
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“Moreover, some apoptotic osteocytes may also be lost during tissue processing because the cells have lost their anchorage to the surrounding lacunar wall [16].”
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“Apoptotic cells were enumerated by trypan blue (Life Technologies) staining (22).”
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“This is consistent with estimates of between 50% and 70% of osteoblasts undergoing apoptosis [64] and the rest differentiating into osteocytes.”
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Self-citationBone Damage in Rheumatoid Arthritis: Mechanistic Insights and Approaches to Prevention
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“TNFα also induced apoptosis of MC3T3-E1 cells when added to cell cultures (59).”
Interleukin-6: An osteotropic factor influencing bone formation?
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Li, Y., Li, A., Strait, K. R., Zhang, H., Nanes, M. S., & Weitzmann, M. N. (2007) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.070121 · Cited by 181
“High doses of TNF have been reported to induce apoptosis of human OBs treated with 1,25(OH)2D3 (38) and in MC3T3-E1 pre-osteoblastic cells.((39)) However, in line with other reports,((8)) we found that TNF did not stimulate apoptosis of MC3T3 cells at”
ResultBorton, A. J., Frederick, J. P., Datto, M., Wang, X.-F., & Weinstein, R. S. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.10.1754 · Cited by 179
“In addition, TUNEL has been used with DNA fragmentation and immunohistochemical studies to show apoptosis of osteoblastic cells and osteoblasts both in vitro and in vivo.((38,40,41)) 1756 BORTON ET AL.”
MethodSelf-citationgp130 CYTOKINE FAMILY AND BONE CELLS
Heymann, D., & Rousselle, A. V. (2000) · Cytokine · doi:10.1006/cyto.2000.0747 · Cited by 173
“IL-6 is a potent anti-apoptotic agent on osteoblastic cells via transcriptional activation of the p21 gene.(56,116) Moreover, IL-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage.”
BackgroundMacrophages and skeletal health
Michalski, M. N., & McCauley, L. K. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.017 · Cited by 171
Haÿ, E., Lemonnier, J., Fromigué, O., & Marie, P. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011265200 · Cited by 171
Bone Loss Triggered by the Cytokine Network in Inflammatory Autoimmune Diseases
Amarasekara, D. S., Yu, J., & Rho, J. (2015) · Journal of Immunology Research · doi:10.1155/2015/832127 · Cited by 177
“At the end of the boneforming phase during bone remodeling, osteoblasts incorporate into the bone as osteocytes and the rest either remain on the bone surface as lining cells or undergo apoptosis [5, 16].”
BackgroundZhou, S., Zilberman, Y., Wassermann, K., Bain, S. D., Sadovsky, Y., & Gazit, D. (2001) · Journal of Cellular Biochemistry · doi:10.1002/jcb.1096 · Cited by 167
“It is known that E2 and growth factors regulate the apoptosis of osteoclasts [Hughes et al., 1996] and osteoblasts [Kitajima et al., 1996a, 1996b; Jilka et al., 1998; Meleti et al., 2000].”
BackgroundRegulation of apoptosis in osteoclasts and osteoblastic cells
Xing, L., & Boyce, B. F. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.11.072 · Cited by 171
Induction of apoptosis in chondrocytes by tumor necrosis factor‐alpha
Aizawa, T., Kon, T., Einhorn, T. A., & Gerstenfeld, L. C. (2001) · Journal of Orthopaedic Research® · doi:10.1016/s0736-0266(00)00078-4 · Cited by 162
Primitive adult hematopoietic stem cells can function as osteoblast precursors
Olmsted‐Davis, E. A., Gugala, Z., Camargo, F. D., Gannon, F. H., Jackson, K., Kienstra, K. A., Shine, H. D., Lindsey, R. W., Hirschi, K. K., Goodell, M. A., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2632959100 · Cited by 160
Significance of Nano- and Microtopography for Cell-Surface Interactions in Orthopaedic Implants
Jäger, M., Zilkens, C., Zanger, K., & Krauspe, R. (2007) · BioMed Research International · doi:10.1155/2007/69036 · Cited by 163
“50 to 70% of all osteoblasts undergo programed cell death (apoptosis) whereas the rest differentiate into osteocytes or persistist as resting or bone-lining cells [10].”
BackgroundThe Biphasic Effects of Nitric Oxide in Primary Rat Osteoblasts Are cGMP Dependent
Mancini, L., Moradi‐Bidhendi, N., Becherini, L., Martineti, V., & Macintyre, I. J. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3164 · Cited by 153
Rojas, E., Carlini, R. G., Clesca, P., Arminio, A., Suniaga, O., Elguezabal, K. D., Weisinger, J. R., Hruska, K. A., & Bellorín-Font, E. (2003) · Kidney International · doi:10.1046/j.1523-1755.2003.00938.x · Cited by 152
Vitamin D and gene networks in human osteoblasts
van de Peppel, J., & van Leeuwen, J. P. T. M. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00137 · Cited by 151
“REVIEW ARTICLE published: 09 April 2014 doi: 10.3389/fphys.2014.00137 Vitamin D and gene networks in human osteoblasts”
BackgroundInfluentialChen, X., Shi, S., Xu, T., Robey, P. G., & Young, M. F. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.2.331 · Cited by 150
“Quantitation of apoptotic cells in culture was estimated also using trypan blue staining.((10)) After 2 weeks of coculture as described previously, the cells were rinsed twice with PBS to remove the feeder cells, incubated with fresh culture medium, and treated with or without Fas-L (1 g/ ml) or STS (10 g/ml) for 48 h…”
BackgroundMethodMackie, P. S., Fisher, J. L., Zhou, H., & Choong, P. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2000.1679 · Cited by 149
“Jilka et al demonstrated th calvarial osteoblast culture and an osteosarcoma cell line cul exhibit background apoptosis, which may be modulated various agents known to be involved in the regulation of Bo Modeling Units (BMUs) (Jilka et al, 1998).”
BackgroundPrevention of Glucocorticoid-Induced Apoptosis in Osteocytes and Osteoblasts by Calbindin-D28k
Liu, Y., Porta, A., Peng, X., Gengaro, K., Cunningham, E. B., Li, H., Dominguez, L. A., Bellido, T., & Christakos, S. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.0301242 · Cited by 148
“The percentage of bone cells exhibiting trypan blue staining has previously been shown to correlate with the percentage of apoptotic cells.((14,23,30)) MLO-Y4 cells or UMR-106 cells were plated on chamber slides and transfected with the expression vectors pREP4 alone or pREP4-calbindin-D28k together with the expressio…”
BackgroundSelf-citationBellido, T., Huening, M., Raval-Pandya, M., Manolagas, S. C., & Christakos, S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003600200 · Cited by 145
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“In contrast, inflammatory cytokines such as IL-1 and TNF- were found to induce osteoblast apoptosis [27, 33, 34], which may contribute to reduce the number of osteoblasts in postmenopausal osteoporosis [30].”
BackgroundKuznetsov, S. A., Cherman, N., Riminucci, M., Collins, M. T., Robey, P. G., & Bianco, P. (2008) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.080609 · Cited by 142
“apoptotic events in bone tissue sections in different species.((15))”
BackgroundIn vitro osteogenesis on a highly bioactive glass‐ceramic (Biosilicate®)
Moura, J., Teixeira, L. N., Ravagnani, C., Peitl, O., Zanotto, E. D., Beloti, M. M., Panzeri, H., Rosa, A. L., & de Oliveira, P. T. (2007) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.31165 · Cited by 141
“The rate of bone formation will mostly be determined by the rate of replication of osteoprogenitors, the number of active osteoblasts, and their life-span.(47,48) Additionally, the enhanced production of bone-like matrix by osteogenic cells grown on Biosilicate(1) could result from the selective recruitment of progeni…”
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Intermittent PTH stimulates periosteal bone formation by actions on post-mitotic preosteoblasts
Jilka, R. L., O’Brien, C. A., Ali, A., Roberson, P. K., Weinstein, R. S., & Manolagas, S. C. (2008) · Bone · doi:10.1016/j.bone.2008.10.037 · Cited by 140
“rate of replication of cancellous osteoblast progenitors combined with the fact that most cancellous osteoblasts die by apoptosis [16,17].”
BackgroundSelf-citationActivation of Caspases Is Required for Osteoblastic Differentiation
Mogi, M., & Togari, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307055200 · Cited by 139
Genetic and Transcriptional Control of Bone Formation
Javed, A., Chen, H., & Ghori-Javed, F. Y. (2010) · Oral and Maxillofacial Surgery Clinics of North America · doi:10.1016/j.coms.2010.05.001 · Cited by 143
Severity of obstructive airway disease and risk of osteoporotic fracture
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Role of inflammation in the aging bones
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Expression of a P2X7 Receptor by a Subpopulation of Human Osteoblasts
Gartland, A., Hipskind, R. A., Gallagher, J. A., & Bowler, W. B. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.5.846 · Cited by 134
“With a low prevalence of apoptosis in osteoblasts, (41)”
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Role of N‐cadherin in bone formation
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Impact of Inflammation on the Osteoblast in Rheumatic Diseases
Baum, R., & Gravallese, E. M. (2013) · Current Osteoporosis Reports · doi:10.1007/s11914-013-0183-y · Cited by 137
TGF-beta1 on osteoimmunology and the bone component cells
Kasagi, S., & Chen, W. (2013) · Cell & Bioscience · doi:10.1186/2045-3701-3-4 · Cited by 131
“For example, TGF-β1 enhances osteoblast proliferation [17], blocks apoptosis of osteoblasts [18], and also recruits osteoblastic precursors or matrix-producing osteoblasts to the site through chemotactic attraction [19].”
BackgroundThe Role of Macrophage in the Pathogenesis of Osteoporosis
Yang, D., & Yang, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092093 · Cited by 144
Metadata
- Authors
- Jilka, R. L., Weinstein, R. S., Bellido, T., Parfitt, A. M., & Manolagas, S. C.
- Affiliations
- University of Arkansas Medical Center (US)
- Corresponding author
- Jilka, Robert L.
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 1998-05-01
- Volume
- 13
- Issue
- 5
- Pages
- 793-802
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2075292460
- Cited by
- 578
- References
- 40
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 19 · 2023: 14 · 2022: 10 · 2021: 17 · 2020: 12 · 2019: 16 · 2018: 21 · 2017: 17 · 2016: 17 · 2015: 17 · 2014: 20 · 2013: 21 · 2012: 24
- FWCI
- 10.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG013918)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- osteoblast apoptosis, programmed cell death, growth factors, cytokines, TGF-beta, interleukin-6, TNF-α, Fas, Bax/Bcl-2 ratio, oncostatin M, bone remodeling, osteocytes, bone lining cells, MC3T3-E1 cells, MG-63 cells, bone microenvironment
- MeSH terms
- Animals, Bone and Bones, Cell Line, Growth Substances, Humans, Osteoblasts, Recombinant Proteins, Tumor Necrosis Factor-alpha, Interleukin-6, Cytokines, Transforming Growth Factor beta, Bone Remodeling, Apoptosis, Receptors, Interleukin-6, Mice
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