Cited by 578Bone Metabolism and DiseasesCell death mechanisms and regulationBone health and osteoporosis research

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Osteoblast Programmed Cell Death (Apoptosis): Modulation by Growth Factors and Cytokines

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Jilka, Robert L., Weinstein, Robert S., Bellido, Teresita, Parfitt, A. Michael, Manolagas, Stavros C.·1998·Journal of Bone and Mineral Research

DOI 10.1359/jbmr.1998.13.5.793

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Abstract

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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Ho, M., Chang, J., Tsai, H., Cho, M.-H., & Wang, G. (2001) · Journal of Musculoskeletal Research · doi:10.1142/s0218957701000623 · Cited by 4
Aging and Bone
Gimble, J. M., Floyd, Z. E., Kassem, M. S., & NUTTALL, M. E. (2016) · Springer eBooks · doi:10.1007/978-3-319-25976-5_2 · Cited by 4
Identification of Matrix Mineralization-Related Genes in Human Periodontal Ligament Cells Using cDNA Microarray
Shin, J.-H., Park, J., Yeo, S.-I., Noh, W.-C., Kim, M., Kim, J.-C., & Suh, J. (2007) · The Journal of the Korean Academy of Periodontology · doi:10.5051/jkape.2007.37.suppl.447 · Cited by 4
Ionic release from bioactive SiO2-CaOCME/poly(tetrahydrofuran)/poly(caprolactone) hybrids drives human-bone marrow stromal cell osteogenic differentiation
Sory, D. R., Heyraud, A. C. M., Jones, J. R., & Rankin, S. M. (2024) · Biomaterials Advances · doi:10.1016/j.bioadv.2024.214019 · Cited by 4
Liquiritigenin suppresses osteoclastogenesis via multi-target mechanisms involving NF-κB/PI3K-AKT signaling pathways and metabolic reprogramming
Zhao, W., Deng, W., Wang, Y., Zhu, R., Liu, J., Chen, H., Tang, W., Luo, Y., Du, A., Zhu, H., et al. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.117678 · Cited by 3
Parathyroid hormone and parathyroid hormone–related protein actions on bone and kidney
Bisello, A., & Friedman, P. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814841-9.00027-0 · Cited by 3
Gene delivery of osteoinductive signals to a human fetal osteoblast cell line induces cell death in a dose-dependent manner
Ramasubramanian, A. M., Jeeawoody, S., & Yang, F. (2013) · Drug Delivery and Translational Research · doi:10.1007/s13346-013-0163-x · Cited by 3
“Osteoblasts at the end of the bone formation process have been reported to undergo apoptosis, suggesting a potential role of osteoblast apoptosis in bone formation and remodeling [17].”
Background
The epigenetic impact of suberohydroxamic acid and 5‑Aza‑2'‑deoxycytidine on DNMT3B expression in myeloma cell lines differing in IL‑6 expression
Trtková, K. S., Luzna, P., Drozdková, D. W., Čížková, K., Janovská, L., Gurský, J., Průková, D., Frydrych, I., Hajdúch, M., & Minařík, J. (2022) · Molecular Medicine Reports · doi:10.3892/mmr.2022.12837 · Cited by 3
Sex hormone-binding globulin promotes the osteogenic differentiation potential of equine adipose-derived stromal cells by activating the BMP signaling pathway
Houston, J. M. I., Bourebaba, L., Bourebaba, N., Tomal, A., & Marycz, K. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1424873 · Cited by 3
“The importance of apoptosis in skeletal tissues and its functional relationship with bone turnover have been recently investigated by various authors to understand whether and, if so, how the mechanism of programmed cell death interferes with bone modelling (23, 25, 26).”
Background
Physiological Regulation of Bone Metabolism and Estrogen Agonism
García‐Pérez, M. Á. (2006) · Springer eBooks · doi:10.1007/3-540-34742-9_7 · Cited by 3
Osteobiology of Aging
Rosenzweig, A. B., & Pignolo, R. J. (2010) · Humana Press eBooks · doi:10.1007/978-1-60327-467-8_1 · Cited by 3
Nitric Oxide and Other Vasoactive Agents
Buttery, L. D. K., Mancini, L., Moradi‐Bidhendi, N., O'Shaughnessy, M. C., Polak, J. M., & MacIntyre, I. M. (2002) · Elsevier eBooks · doi:10.1016/b978-012098652-1.50157-8 · Cited by 3
In Vitro Regulation of Osteoblast Activity
Karin, N. J., & Farach‐Carson, M. C. (2004) · Springer eBooks · doi:10.1007/978-1-4471-3777-1_2 · Cited by 3
Kinins : important regulators in inflammation induced bone resorption
Brechter, A. B. (2006) · Cited by 3
Modeling Early Stages of Bone and Joint Infections Dynamics in Humans: A Multi-Agent, Multi-System Based Model
Alsassa, S., Lefèvre, T., Laugier, V., Stindel, É., & Ansart, S. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00026 · Cited by 2
Basics of Bone Biology
Rauner, M., & Hofbauer, L. C. (2016) · Springer eBooks · doi:10.1007/978-3-319-34238-2_1 · Cited by 2
HIF-1α activation impairs dendrites formation and elongation in osteocytogenesis
Li, X., Zhao, J. H., Chen, L., Zhou, X., Qiu, M., Deng, L., Yang, K., & Xu, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e32889 · Cited by 2
“At the final stage of bone formation, osteoblasts may enter a dormant state as bone lining cells, or undergo programmed cell death, or become deeply embedded in osteoid, where they differentiate into osteocytes [1,2].”
Exploring the Osteoinductive Potential of Bacterial Pyomelanin Derived from Pseudomonas aeruginosa in a Human Osteoblast Model
Urbaniak, M. M., Rudnicka, K., Płociński, P., & Chmiela, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413406 · Cited by 2
Biochemical and functional properties of mammalian bone alkaline phosphatase isoforms during osteogenesis
Linder, C. H. (2016) · Linköping University medical dissertations · doi:10.3384/diss.diva-127100 · Cited by 3
“When an osteoblast stops forming bone, it has three ways to go: i) it can be embedded into the bone matrix and differentiate to an osteocyte [32], ii) it can stay on the bone surface and differentiate to a bone lining cell [33] or, iii) it can undergo programmed cell death (apoptosis) [13].”
Cell Survival and Death in Rheumatic Diseases
Elkon, K. B. (2013) · Elsevier eBooks · doi:10.1016/b978-1-4377-1738-9.00027-x · Cited by 2
Effect of Cyanobacteria (Nostoc species) Extracts on Osteogenesis Activities
Chamnanpuen, P., Satitpatipan, V., Sirisattha, S., & Muangman, T. (2020) · Walailak Journal of Science and Technology (WJST) · doi:10.48048/wjst.2020.5350 · Cited by 2
“At the end of the bone formation phase, osteoblasts can either become embedded in bone as osteocytes, become inactive osteoblasts or bone lining cells [21], or undergo programmed cell death (apoptosis) [21,22].”
Background
Osteoblast Biology
Lian, J. B., & Stein, G. S. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-375098-3.50007-x · Cited by 2
Osteoimmunology: The Bone-Immune Crosstalk
Chiappelli, F. (2011) · Springer eBooks · doi:10.1007/978-1-4419-9495-0_1 · Cited by 2
Immunology of Osteoporosis
Kerschan‐Schindl, K., Nebot, E., & Pietschmann, P. (2018) · Springer eBooks · doi:10.1007/978-3-319-64597-1_153-1 · Cited by 2
Effects of Nonsteroidal Anti‐Inflammatory Drugs on Transforming Growth Factor‐β Expression and Bioactivity in Rat Osteoblast‐Enriched Cultures
Chang, J., Wang, G., Chuang, L., & Ho, M. (2003) · The Kaohsiung Journal of Medical Sciences · doi:10.1016/s1607-551x(09)70474-7 · Cited by 2
“Furthermore, TGF-β has an anti-apoptotic effect in osteoblasts [17].”
Background
Inflammatory Periprosthetic Bone Loss
Lee, S., Edward, P., & Nam, J. (2012) · InTech eBooks · doi:10.5772/25558 · Cited by 1
“…[OB] Effects on osteoclasts [OC] TNF Induces RANKL & M-CSF (Wei et al., 2005) Inhibits OB differentiation & apoptosis (Gilbert et al., 2000; Jilka et al., 1998) Increases OC precursor numbers (Li et al., 2004; Yao et al., 2006) Acts synergistically with RANKL (Lam et al., 2000) IL-1 …”
Background
Arg972 insulin receptor substrate-1 enhances tumor necrosis factor-α-induced apoptosis in osteoblasts
You, Y., Liu, S., Peng, L., LONG, M., DENG, H., & Zhao, H. (2012) · Molecular Medicine Reports · doi:10.3892/mmr.2015.3457 · Cited by 1
Activation of cellular responses to interleukin 6 is blocked by staurosporine
Peppard, J. (1999) · Immunopharmacology · doi:10.1016/s0162-3109(99)00083-1 · Cited by 1
Molecular Bases of Osteoporosis in HIV: The Role of the Virus and Antiretroviral Therapy
Gibellini, D., Borderi, M., Vanino, E., Clò, A., Morini, S., Calza, L., Re, M. C., & Viale, P. (2012) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1007/s12018-012-9133-y · Cited by 1
“In fact, TNF-alpha is an inducer of osteoclast activity and can determine the survival impairment of osteoblasts, whereas IL-6 is involved in the osteoclast differentiation enhancement in presence of M-CSF and RANKL induction [52, 70, 71].”
Background
The Variety of Osteocyte Function
O’Brien, C. A. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800571-2.00006-2 · Cited by 1
Bone — Normal Structure and Physiology
Monier‐Faugere, M., Sawaya, B. P., Langub, M. C., & Malluche, H. H. (2002) · Springer eBooks · doi:10.1007/978-1-4471-0667-8_16 · Cited by 1
Cell Survival and Death in Rheumatic Diseases
Elkon, K. B. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-3285-4.10024-5 · Cited by 1
Cytokines and Bone Remodeling
Mundy, G. R., Oyajobi, B. O., Gutierrez, G., Sterling, J. A. R., Padalecki, S. S., Elefteriou, F., & Zhao, M. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-375098-3.50019-6 · Cited by 1

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.
ORCID: Weinstein, Robert S.
Bellido, Teresita
Manolagas, Stavros C.
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
DOI: 10.1359/jbmr.1998.13.5.793
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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Osteoblast Programmed Cell Death (Apoptosis): Modulation by Growth Factors and Cytokines

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