Cited by 176Bone Metabolism and DiseasesCell death mechanisms and regulationOsteoarthritis Treatment and Mechanisms

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Cell Death in Chondrocytes, Osteoblasts, and Osteocytes

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Komori, Toshihisa·2016·International Journal of Molecular Sciences

DOI 10.3390/ijms17122045PMC PMC5187845

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Abstract

Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation of P53 and RB is involved in the pathogenesis of osteosarcomas, the deletion of p53 and inactivation of Rb are insufficient to enhance chondrocyte proliferation, indicating the presence of multiple inhibitory mechanisms against sarcomagenesis in chondrocytes. The inflammatory processes induced by mechanical injury and chondrocyte death through the release of danger-associated molecular patterns (DAMPs) are involved in the pathogenesis of posttraumatic osteoarthritis. The overexpression of BCLXL increases bone volume with a normal structure and maintains bone during aging by inhibiting osteoblast apoptosis. p53 inhibits osteoblast proliferation and enhances osteoblast apoptosis, thereby reducing bone formation, but also exerts positive effects on osteoblast differentiation through the Akt–FoxOs pathway. Apoptotic osteocytes release ATP, which induces the receptor activator of nuclear factor κ-B ligand (Rankl) expression and osteoclastogenesis, from pannexin 1 channels. Osteocyte death ultimately results in necrosis; DAMPs are released to the bone surface and promote the production of proinflammatory cytokines, which induce Rankl expression, and osteoclastogenesis is further enhanced.

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Figure 1 Chondrocyte death in osteoarthritis. Mechanical injury, the loss of the extracellular matrix, loss of growth factors, and excessive levels of reactive oxygen species (ROS) induce chondrocyte death in articular cartilage. Chondrocyte hypertrophy in articular cartilage induces the destruction of the cartilage matrix through the induction of matrix metalloproteinases (MMPs) and aggrecanases, and leads to chondrocyte apoptosis. The number of dead chondrocytes also increases in articular cartilage during aging. DAMPs (danger-associated molecular patterns) released by mechanical injury and chondrocyte secondary necrosis initiate non-infectious inflammatory responses through PRRs (pattern recognition receptors) expressed in osteoarthritis (OA) cartilage and the synovium, causing complement activation, oxidative stress, impaired mitochondrial function, and the induction of MMPs and aggrecanases. Complement activation, an increase in nitric oxide (NO) and ROS, a decrease in mitochondrial ATP, and endoplasmic reticulum (ER) stress further enhance chondrocyte death, resulting in the progression of osteoarthritis. The contribution of chondrocyte death to inflammatory processes needs to be evaluated. The inflammatory processes induced by mechanical injury contribute to the development of posttraumatic OA; however, their significance in non-posttraumatic OA remains unclear.CC BY · PubMed Central

Figure 2 Acceleration of osteoblast differentiation through the p53–Akt–FoxO pathway. p53 induces the expression of Igfbp3 and Pten. Igfbp3 inhibits IGF/insulin binding to the receptor, and Pten dephosphorylates PIP3 to PIP2. PIP3 recruits Akt to the cell membrane and Akt is activated by PDK1 and mTORC2. The decrease in PIP3 inactivates Akt. Akt regulates metabolism, cell growth, cell survival, cell proliferation, and cell differentiation through GSK3, mTORC1, and FoxOs. Akt phosphorylates FoxOs to inactivate them. FoxOs are involved in cell cycle arrest, apoptosis, DNA repair, anti-oxidative stress, and osteoblast differentiation.CC BY · PubMed Central

Figure 3 Induction of bone resorption by ATP released from apoptotic osteocytes. In apoptotic osteocytes, active Panx1 channels, which release ATP, are formed by the caspase-mediated cleavage of the C terminus. P2X7 receptor (P2X7R), which is activated by extracellular ATP, forms a complex with Panx1 and enhances ATP release. Extracellular ATP recruits macrophages and monocytes through P2Y2R, increases nuclear factor κ-B ligand (Rankl) expression in osteocytes through P2X7R and in osteoblasts through P2Y1R, increases osteoclast survival through P2Y6R, and enhances the membrane fusion of osteoclast precursor cells to form multinucleated osteoclasts through P2X7R. The up-regulation of Rankl in osteocytes will reduce the release of osteoprotegerin (Opg), which is secreted by osteocytes, to the bone surface. It has been shown that Panx1 and P2X7R are required for Rankl up-regulation in osteocytes in fatigued bone. However, the functions of ATP released from apoptotic osteocytes shown here have not yet been directly proven in damaged bone.CC BY · PubMed Central

Figure 4 A proposed scheme for the enhanced osteoclastogenesis by osteocyte death. Any type of osteocyte death ultimately results in necrosis because dead osteocytes are not phagocytosed. DAMPs (danger-associated molecular patterns) released from necrotic osteocytes pass through canaliculi and reach the bone surface. Macrophages, dendritic cells, neutrophils, and monocytes are stimulated by DAMPs through PRRs (pattern recognition receptors), and produce TNFα, IL-6, and IL-1, which stimulate the expression of Rankl in osteoblast lineage cells. Osteoclast precursors differentiate into osteoclasts through Rankl-Rank signaling. Opg released from osteocytes to the bone surface negatively regulates osteoclastogenesis and osteoclast activity. This scheme is predicted from previous studies, but has not been directly proven in damaged bone.CC BY · PubMed Central

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Connexins, pannexins, innexins: novel roles of “hemi-channels”
Scemes, E., Spray, D. C., & Meda, P. (2008) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-008-0591-5 · Cited by 203 · cited 1×
“Two junctional proteins—connexins and pannexins—form membrane channels permeable to large molecules in vertebrates [94].”
Background
Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on Toll-like receptor 4.
Schelbergen, R., Blom, A., van den Bosch, M. V. D., Slöetjes, A., Abdollahi-Roodsaz, S., Schreurs, B. W., Mort, J., Vogl, T., Roth, J., van den Berg, W., et al. (2012) · Arthritis & Rheumatism · doi:10.1002/art.33495 · Cited by 195 · cited 1×
“The signaling pathway through PRRs induces synovitis, transduces inflammation, increases the expression of matrix metalloproteinases (MMPs) and aggrecanases, and induces oxidative stress and cell death [55,56].”
Background
Structure and Development of the Skeleton
Marks, S. C., & Odgren, P. R. (2002) · Elsevier eBooks · doi:10.1016/b978-012098652-1.50103-7 · Cited by 194 · cited 2×
“Both communication systems are extended to osteoblasts on the bone surface [93].”
Background
Chondrocyte apoptosis: a cause or consequence of osteoarthritis?
Zamli, Z., & Sharif, M. (2011) · International Journal of Rheumatic Diseases · doi:10.1111/j.1756-185x.2011.01618.x · Cited by 178 · cited 1×
“A number of processes, including chondrocyte hypertrophy, inflammatory processes, and chondrocyte death, are involved in the pathogenesis of OA [9,30,31].”
Background
Increased apoptosis in human osteoarthritic cartilage corresponds to reduced cell density and expression of caspase‐3
Sharif, M., Whitehouse, A., Sharman, P., Perry, M., & Adams, M. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20020 · Cited by 173
Control of RANKL gene expression
O’Brien, C. A. (2009) · Bone · doi:10.1016/j.bone.2009.08.050 · Cited by 170
Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis
DʼLima, D. D., Hermida, J. C., Hashimoto, S., Colwell, C. W., & Lotz, M. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21874 · Cited by 169 · cited 1×
“The intra-articular administration of caspase inhibitors has been shown to inhibit chondrocyte death and cartilage degradation in OA rabbit models [46,47].”
Background
Accelerated, aging‐dependent development of osteoarthritis in α1 integrin–deficient mice
Zemmyo, M., Meharra, E. J., Kühn, K., Creighton‐Achermann, L., & Lotz, M. (2003) · Arthritis & Rheumatism · doi:10.1002/art.11246 · Cited by 159 · cited 2×
“proteins to various intracellular cytoskeletal proteins [53].”
Background
How severe must repetitive loading be to kill chondrocytes in articular cartilage?
Clements, K. M., Bee, Z. C., Crossingham, G. V., Adams, M. A., & Sharif, M. (2001) · Osteoarthritis and Cartilage · doi:10.1053/joca.2000.0417 · Cited by 152
Bone microdamage and cell apoptosis
Noble, B. (2003) · European Cells and Materials · doi:10.22203/ecm.v006a05 · Cited by 152 · cited 1×
“The microdamage of bone has been associated with osteocyte apoptosis and targeted bone resorption [105,106].”
Background
Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo
Kennedy, O. D., Laudier, D. M., Majeska, R. J., Sun, H. B., & Schaffler, M. B. (2014) · Bone · doi:10.1016/j.bone.2014.03.049 · Cited by 151
Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis
Teixeira, C. C., Liu, Y., Thant, L. M., Pang, J., Palmer, G. D., & Alikhani, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.079962 · Cited by 150
A Distinct “Side Population” of Cells in Human Tumor Cells: Implications for Tumor Biology and Therapy
Hirschmann-Jax, C., Foster, A. E., Wulf, G. G., Goodell, M. A., & Brenner, M. K. (2004) · Cell Cycle · doi:10.4161/cc.4.2.1406 · Cited by 147
Cell signals transduced by complement
Bohana‐Kashtan, O. (2004) · Molecular Immunology · doi:10.1016/j.molimm.2004.04.007 · Cited by 145 · cited 1×
“Complement may be activated by DAMPs, and activated complement components may induce chondrocyte death [62,63].”
Background
TGFβ and PTHrP Control Chondrocyte Proliferation by Activating Cyclin D1 Expression
Beier, F., Ali, Z., Mok, D., Taylor, A. C., Leask, T., Albanese, C., Pestell, R. G., & Luvalle, P. A. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.12.3852 · Cited by 137 · cited 1×
“In the growth plate, Cyclin D1 is strongly expressed in the proliferating layer [15], and Cyclin D1-deficient mice show dwarfism with a diminished proliferating layer in the growth plate [13,15,17,18].”
Background
SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin‐like growth factor receptor pathway
Gagarina, V., Gabay, O., Dvir‐Ginzberg, M., Lee, E. J., Brady, J. K., Quon, M. J., & Hall, D. J. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27369 · Cited by 137
Effect of nitric oxide on mitochondrial respiratory activity of human articular chondrocytes
Maneiro, E., López-Armada, M. J., de Andres, M. C., Caramés, B., Martín, M. A., Bonilla, A., del Hoyo, P., Galdo, F., Arenas, J., & Blanco, F. J. (2005) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2004.022152 · Cited by 134
Glucocorticoid Signaling and Bone Biology
Komori, T. (2016) · Hormone and Metabolic Research · doi:10.1055/s-0042-110571 · Cited by 131 · cited 2×
“Excess GCs increase the levels of the pro-apoptotic factors, Bim and Bak; decrease that of the pro-survival factor, BclXL; up-regulate the expression of the p53 protein; increase ROS levels; inhibit Akt; and enhance ER stress [35].”
BackgroundSelf-citation
Endoplasmic reticulum stress-induced apoptosis contributes to articular cartilage degeneration via C/EBP homologous protein
Uehara, Y., Hirose, J., Yamabe, S., Okamoto, N., Okada, T., Oyadomari, S., & Mizuta, H. (2014) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2014.04.025 · Cited by 124 · cited 1×
“Furthermore, oxidative stress and mitochondrial dysfunction cause endoplasmic reticulum (ER) stress, and the unsuccessful resolution of ER stress by the unfolded protein response (UPR) promotes chondrocyte apoptosis via Chop [64] (Figure 1).”
Background
Influence of tissue maturation and antioxidants on the apoptotic response of articular cartilage after injurious compression
Kurz, B., Lemke, A. K., Kehn, M., Domm, C., Patwari, P., Frank, E. H., Grodzinsky, A. J., & Schünke, M. (2004) · Arthritis & Rheumatism · doi:10.1002/art.11438 · Cited by 123
Functions of the osteocyte network in the regulation of bone mass
Komori, T. (2013) · Cell and Tissue Research · doi:10.1007/s00441-012-1546-x · Cited by 113 · cited 13×
“Regulation of the Release of Osteocyte-Derived Opg to the Bone Surface May Be a Major Role for Rankl on Osteocytes Osteocytes strongly express Rankl and Opg, which is a secreted decoy receptor of Rankl [120–122].”
BackgroundInfluentialSelf-citation
P2Y6 Nucleotide Receptors Activate NF-κB and Increase Survival of Osteoclasts
Korčok, J., Raimundo, L., Du, X., Sims, S. M., & Dixon, S. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m410764200 · Cited by 112
Apoptosis of Chondrocytes in Transgenic Mice Lacking Collagen II
Yang, C., Li, S.-W., Helminen, H. J., Khillan, J. S., Bao, Y., & Prockop, D. J. (1997) · Experimental Cell Research · doi:10.1006/excr.1997.3692 · Cited by 112
Differential Roles of Two Tandem E2F Sites in Repression of the Human p107 Promoter by Retinoblastoma and p107 Proteins
Zhu, L., Zhu, L., Xie, E., & Chang, L. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.7.3552 · Cited by 112
Connexin 43 Channels Are Essential for Normal Bone Structure and Osteocyte Viability
Xu, H., Gu, S., Riquelme, M. A., Burra, S., Callaway, D. A., Cheng, H., Guda, T., Schmitz, J. E., Fajardo, R. J., Werner, S. L., et al. (2014) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2374 · Cited by 108 · cited 1×
“Osteocyte ablation by diphtheria toxin, the deletion of Gja1 (connexin 43), which constitutes gap junction channels and hemichannels, and osteocyte-specific transgenic mice expressing mutant Gja1, which blocks gap junction channels and hemichannels, cause osteocyte apoptosis, leading to secondary necrosis, enhanced bo…”
Background
Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice
Gabay, O., Oppenhiemer, H., Meir, H., Zaal, K. J. M., Sanchez, C., & Dvir‐Ginzberg, M. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2011.200504 · Cited by 107
Cell death in osteoarthritis
Carlo, M. D., & Loeser, R. F. (2008) · Current Rheumatology Reports · doi:10.1007/s11926-008-0007-8 · Cited by 106 · cited 4×
“Chondrocyte Death during Mechanical Injury May Contribute to the Development of OA Chondrocyte death may be induced by mechanical injury, the loss of the extracellular matrix, loss of growth factors, or excessive levels of reactive oxygen species (ROS) [49] (Figure 1).”
BackgroundInfluential
Osteocyte Network; a Negative Regulatory System for Bone Mass Augmented by the Induction of Rankl in Osteoblasts and Sost in Osteocytes at Unloading
Moriishi, T., Fukuyama, R., Ito, M., Miyazaki, T., Maeno, T., Kawai, Y., Komori, H., & Komori, T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040143 · Cited by 105 · cited 2×
“In BCl2 transgenic mice, osteocyte death does not induce bone resorption because the extracellular communication system is also disrupted [120].”
BackgroundSelf-citation
Adenosine triphosphate stimulates human osteoclast activity via upregulation of osteoblast-expressed receptor activator of nuclear factor-κB ligand
Buckley, K. M., Hipskind, R. A., Gartland, A., Bowler, W. B., & Gallagher, J. A. (2002) · Bone · doi:10.1016/s8756-3282(02)00877-3 · Cited by 98
Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis
Zhang, M., Mani, S. B., He, Y., Hall, A. M., Xu, L., Li, Y., Zurakowski, D., Jay, G. D., & Warman, M. L. (2016) · Journal of Clinical Investigation · doi:10.1172/jci83676 · Cited by 95 · cited 2×
“However, the significance of the DAMPs released from necrotic chondrocytes still needs to be investigated because the ablation of chondrocytes by diphtheria toxin prior to the operation for surgical OA reduces cartilage damage [48].”
BackgroundResult
Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway
Li, T.-F., Dong, Y., Ionescu, A. M., Rosier, R. N., Zuscik, M. J., Schwarz, E. M., O’Keefe, R. J., & Drissi, H. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.05.025 · Cited by 94
Pannexin-1 and P2X7-Receptor Are Required for Apoptotic Osteocytes in Fatigued Bone to Trigger RANKL Production in Neighboring Bystander Osteocytes
Cheung, W. Y., Fritton, J. C., Morgan, S. A., Seref-Ferlengez, Z., Basta-Pljakic, J., Thi, M. M., Suadicani, S. O., Spray, D. C., Majeska, R. J., & Schaffler, M. B. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2740 · Cited by 89 · cited 3×
“Since bone resorption after osteocyte apoptosis is attenuated in Panx1−/− mice [110], the release of ATP from Panx1 channels appears to be a prerequisite for bone resorption.”
BackgroundInfluential
FOXO1 modulates osteoblast differentiation
Siqueira, M. F., Flowers, S. J., Bhattacharya, R., Faibish, D., Behl, Y., Kotton, D. N., Gerstenfeld, L. C., Morán, E., & Graves, D. T. (2011) · Bone · doi:10.1016/j.bone.2011.01.019 · Cited by 88
Chondrocyte death during murine osteoarthritis
Mistry, D., Oue, Y., Chambers, M. G., Kayser, M. V., & Mason, R. M. (2003) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2003.10.006 · Cited by 87
G1 Cyclin/Cyclin-dependent Kinase-coordinated Phosphorylation of Endogenous Pocket Proteins Differentially Regulates Their Interactions with E2F4 and E2F1 and Gene Expression
Calbó, J., Parreño, M., Sotillo, E., Yong, T., Mazo, A., Garriga, J., & Graña, X. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m209181200 · Cited by 87
Runx2 expression and action in chondrocytes are regulated by retinoid signaling and parathyroid hormone-related peptide (PTHrP)
Iwamoto, M., Kitagaki, J., Tamamura, Y., Gentili, C., Koyama, E., Enomoto, H., Komori, T., Pacifici, M., & Enomoto‐Iwamoto, M. (2002) · Osteoarthritis and Cartilage · doi:10.1053/joca.2002.0860 · Cited by 86
Self-citation
Dysapoptosis of Osteoblasts and Osteocytes Increases Cancellous Bone Formation But Exaggerates Cortical Porosity With Age
Jilka, R. L., O’Brien, C. A., Roberson, P. K., Bonewald, L. F., Weinstein, R. S., & Manolagas, S. C. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2007 · Cited by 85 · cited 1×
“The deletion of Bak and Bax in osteoblasts also increases the mineral density and trabecular bone volume of femurs, whereas the cortical bone volume of femurs and cancellous bone volume of vertebrae are not increased and cortical bone shows severe porosity in aged mice [77].”
Background
Measurement of urinary excretion of nonisomerized and ?-isomerized forms of type I collagen breakdown products to monitor the effects of the bisphosphonate zoledronate in Paget's disease
Garnero, P., Gineyts, É., Schaffer, A. V., Seaman, J. J., & Delmas, P. D. (1998) · Arthritis & Rheumatism · doi:10.1002/1529-0131(199802)41:2 · Cited by 79
In vivo regulation of apoptosis in metaphyseal trabecular bone of young rats by synthetic human parathyroid hormone (1-34) fragment
Stanislaus, D., Yang, X., Liang, J., Wolfe, J. M. T., Cain, R. L., Onyia, J. E., Falla, N., Marder, P., Bidwell, J. P., Queener, S. W., et al. (2000) · Bone · doi:10.1016/s8756-3282(00)00309-4 · Cited by 72
A transgenic mouse model with cyclin D1 overexpression results in cell cycle, epidermal growth factor receptor, and p53 abnormalities.
Mueller, A., Odze, R. D., Jenkins, T. D., Shahsesfaei, A., Nakagawa, H., Inomoto, T., & Rustgi, A. K. (1997) · PubMed · Cited by 70
Characterization of mature vs aged rabbit articular cartilage: analysis of cell density, apoptosis-related gene expression and mechanisms controlling chondrocyte apoptosis
Allen, R. T., Robertson, C. M., Harwood, F. L., Sasho, T., Williams, S. K., Pomerleau, A. C., & Amiel, D. (2004) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2004.08.003 · Cited by 68 · cited 1×
“Furthermore, a significant decrease has been reported in chondrocyte numbers in articular cartilage with aging [39,44,45].”
Background
p107 and p130 Coordinately Regulate Proliferation, Cbfa1 Expression, and Hypertrophic Differentiation during Endochondral Bone Development
Rossi, F., MacLean, H. E., Yuan, W., Francis, R. O., Semenova, E., Lin, C. S., Kronenberg, H. M., & Cobrinik, D. E. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0691 · Cited by 68 · cited 2×
“Rb family proteins play an important role in chondrocyte proliferation and differentiation [19,20].”
Background
Overexpression of Bcl2 in Osteoblasts Inhibits Osteoblast Differentiation and Induces Osteocyte Apoptosis
Moriishi, T., Maruyama, Z., Fukuyama, R., Ito, M., Miyazaki, T., Kitaura, H., Ohnishi, H., Furuichi, T., Kawai, Y., Masuyama, R., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027487 · Cited by 68 · cited 7×
“Osteoblastogenesis in BCL2-overexpressing primary osteoblasts in vitro is also controversial, and was previously reported to be enhanced and inhibited [81].”
BackgroundInfluentialSelf-citation
Estrogen Prevents Glucocorticoid-Induced Apoptosis in Osteoblasts in Vivo and in Vitro
Gohel, A. (1999) · Endocrinology · doi:10.1210/en.140.11.5339 · Cited by 68
Anti-apoptotic Molecule Bcl-2 Regulates the Differentiation, Activation, and Survival of Both Osteoblasts and Osteoclasts
Nagase, Y., Iwasawa, M., Akiyama, T., Kadono, Y., Nakamura, M., Oshima, Y., Yasui, T., Matsumoto, T., Hirose, J., Nakamura, H., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.016915 · Cited by 59 · cited 2×
“In vitro osteoblast cultures also showed that the differentiation of Bcl2−/− osteoblasts was similar to or impaired more than that of wild-type osteoblasts [78,79].”
BackgroundResult
Chondrocyte cell death mediated by reactive oxygen species-dependent activation of PKC-betaI.
Delcarlo, M., & Loeser, R. (2006) · American Journal of Physiology - Cell Physiology · doi:10.1152/ajpcell.00214.2005 · Cited by 56
Role of Bcl2 in Osteoclastogenesis and PTH Anabolic Actions in Bone
Yamashita, J., Datta, N. S., Chun, Y. P., Yang, D.-Y., Carey, A. A., Kreider, J. M., Goldstein, S. A., & McCauley, L. K. (2007) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.071211 · Cited by 55 · cited 2×
“In vitro osteoblast cultures also showed that the differentiation of Bcl2−/− osteoblasts was similar to or impaired more than that of wild-type osteoblasts [78,79].”
BackgroundResult
The P2X7 Receptor and Pannexin-1 Are Both Required for the Promotion of Multinucleated Macrophages by the Inflammatory Cytokine GM-CSF
Lemaire, I. B., Falzoni, S., Zhang, B., Pellegatti, P., & Virgilio, F. D. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002780 · Cited by 53
Disruption of the p53 Gene Results in Preserved Trabecular Bone Mass and Bone Formation After Mechanical Unloading
Sakai, A., Sakata, T., Tanaka, S., Okazaki, R., Kunugita, N., Norimura, T., & Nakamura, T. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.1.119 · Cited by 48
Bcl2 Deficiency Activates FoxO through Akt Inactivation and Accelerates Osteoblast Differentiation
Moriishi, T., Kawai, Y., Komori, H., Rokutanda, S., Eguchi, Y., Tsujimoto, Y., Asahina, I., & Komori, T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086629 · Cited by 47 · cited 9×
“The inhibition of osteoblast proliferation in Bcl2−/− mice is, at least in part, due to the up-regulation of p53 and FoxOs [80].”
BackgroundResultInfluentialSelf-citation
BCL2 inhibits cell adhesion, spreading, and motility by enhancing actin polymerization
Ke, H., Parron, V. I., Reece, J. M., Zhang, J. Y., Akiyama, S. K., & French, J. E. (2010) · Cell Research · doi:10.1038/cr.2010.21 · Cited by 45 · cited 1×
“3-kb Col1a1 promoter because the osteocyte processes and canaliculi are severely reduced, possibly due to the formation of a complex of BCL2, actin, and gelsolin, which reduces gelsolin-severing activity in order to increase actin polymerization [81,119].”
Background
Impaired Vascular Invasion of Cbfa1-Deficient Cartilage Engrafted in the Spleen
Himeno, M., Enomoto, H., Liu, W., Ishizeki, K., Nomura, S., Kitamura, Y., & Komori, T. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.7.1297 · Cited by 44
Self-citation
ATP P2 receptors and regulation of bone effector cells.
Gallagher, J. A. (2004) · PubMed · Cited by 41
Tandem E2F Binding Sites in the Promoter of the p107 Cell Cycle Regulator Control p107 Expression and Its Cellular Functions
Burkhart, D. L., Wirt, S. E., Zmoos, A., Kareta, M. S., & Sage, J. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001003 · Cited by 38
PIM‐2 is an independent regulator of chondrocyte survival and autophagy in the epiphyseal growth plate
Bohensky, J., Shapiro, I. M., Leshinsky, S., Watanabe, H., & Srinivas, V. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21117 · Cited by 36 · cited 1×
“Similar to osteocytes, autophagy also protects chondrocytes from apoptosis, and its failure leads to apoptosis [35,36].”
Background
Morphology of sites of adhesion between hepatic stellate cells (vitamin A-storing cells) and a three-dimensional extracellular matrix
Imai, K., & Senoo, H. (1998) · The Anatomical Record · doi:10.1002/(sici)1097-0185(199804)250:4 · Cited by 34
Beneficial effects of intra-articular caspase inhibition therapy following osteochondral injury
Dang, A. C., Warren, A. P., & Kim, H. T. (2006) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2005.12.010 · Cited by 33 · cited 1×
“The intra-articular administration of caspase inhibitors has been shown to inhibit chondrocyte death and cartilage degradation in OA rabbit models [46,47].”
Background
Development of the chick olfactory nerve
Vermeer, P. D., & Silverman, A. (1999) · Developmental Dynamics · doi:10.1002/(sici)1097-0177(199904)214:4 · Cited by 33
Self-citation
Overexpression of BCLXL in Osteoblasts Inhibits Osteoblast Apoptosis and Increases Bone Volume and Strength
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 · cited 2×
“The bone structure is similar to, but stronger than that in wild-type mice and the increased bone mass is maintained during aging in both sexes [76].”
BackgroundSelf-citation
Revisiting the “Cdk-Centric” View of the Mammalian Cell Cycle
Malumbres, M. (2004) · Cell Cycle · doi:10.4161/cc.4.2.1410 · Cited by 32 · cited 1×
“Cyclin D activates Cdk4 and Cdk6 in the G1 phase, cyclin E activates Cdk2 in the G1/S phase, cyclin A activates Cdk2 and Cdk1 in the S phase, and cyclin B activates Cdk1 in the M phase [12].”
Background
Overexpression of Cdk6 and Ccnd1 in chondrocytes inhibited chondrocyte maturation and caused p53-dependent apoptosis without enhancing proliferation
Ito, K., Maruyama, Z., Sakai, A., Izumi, S., Moriishi, T., Yoshida, C. A., Miyazaki, T., Komori, H., Takada, K., Kawaguchi, H., et al. (2013) · Oncogene · doi:10.1038/onc.2013.130 · Cited by 30 · cited 6×
“Rb is highly phosphorylated, while unphosphorylated p107 levels are elevated in Cdk6/Cyclin D1 double transgenic mice [21].”
BackgroundInfluentialSelf-citation
Cdkn2a encodes functional variation of p16INK4a but not p14ARF, which confers selection in mouse lung tumorigenesis
Herzog, C. R., Noh, S. J., Lantry, L. E., Guan, K.-L., & You, M. (1999) · Molecular Carcinogenesis · doi:10.1002/(sici)1098-2744(199906)25:2 · Cited by 26
Cyclic Loading Can Denature Type II Collagen in Articular Cartilage
Clements, K. M., Hollander, A. P., Sharif, M., & Adams, M. A. (2004) · Connective Tissue Research · doi:10.1080/03008200490514121 · Cited by 21
Regulation of Rb family proteins by Cdk6/Ccnd1 in growth plates
Komori, T. (2013) · Cell Cycle · doi:10.4161/cc.25515 · Cited by 14 · cited 1×
“Under physiological conditions, unphosphorylated p107 associates with repressing E2fs, whereas unphosphorylated p107 also associates with activating E2fs when p107 is up-regulated, resulting in the dysregulation of E2f target gene expression, as reported in Cdk6/Cyclin D1 double transgenic mice [28,29].”
BackgroundSelf-citation
Loss of pRB and p107 disrupts cartilage development and promotes enchondroma formation
Landman, A. S., Danielian, P. S., & Lees, J. A. (2012) · Oncogene · doi:10.1038/onc.2012.496 · Cited by 13 · cited 1×
“in p107−/−p130−/− or p107−/−Rb−/− mice and chondrocyte proliferation also increases without elevations in chondrocyte apoptosis [19,20,27].”
Trabecular bone mass and bone formation are preserved after limb immobilisation in p53 null mice
Okazaki, R., Sakai, A., Ootsuyama, A., Sakata, T., Nakamura, T., & Norimura, T. (2004) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2003.011643 · Cited by 8

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“These apoptotic osteocytes further induced Rankl expression and osteoclastogenesis, which resulted in increased bone resorption and bone mass loss.(176) Interestingly, in experimental animals, treatment with an apoptosis inhibitor (the pancaspase inhibitor QVD-OPh) rescued osteocyte cell loss and bone mass reduction d…”
Background
Bone remodeling: an operational process ensuring survival and bone mechanical competence
Bolamperti, S., Villa, I., & Rubinacci, A. (2022) · Bone Research · doi:10.1038/s41413-022-00219-8 · Cited by 482
“Necrotic osteocytes release damage-associated molecular pattern (DAMP) proteins after the cell membrane is disrupted.(61) DAMP proteins flow through the canalicular network and reach the bone/marrow interface, where they bind to pattern recognition receptors (PRRs) on bone marrow cells.”
Background
The Regulation of Bone Metabolism and Disorders by Wnt Signaling
Maeda, K., Kobayashi, Y., Koide, M., Uehara, S., Okamoto, M., Ishihara, A., Kayama, T., Saito, M., & Marumo, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225525 · Cited by 360
“OA is a degenerative disease associated with articular cartilage damage, osteophyte formation, and hardening of the subchondral bone [152,153].”
Background
Regulation and Role of Transcription Factors in Osteogenesis
Chan, W. C. W., Tan, Z., To, M. K.-T., & Chan, D. T.-M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115445 · Cited by 276
“p53 and FoxOs have similar functions in inhibiting cell cycles and inducing cell death in osteoblasts [141].”
Background
Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin
Andreev, D., Liu, M., Weidner, D., Kachler, K., Faas, M., Grüneboom, A., Schlötzer-Schrehardt, U., Muñoz, L. E., Steffen, U., Grötsch, B., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134214 · Cited by 188
“However, because phagocytes cannot reach and engulf apoptotic osteocytes in their isolated lacunae, these cells automatically undergo secondary necrosis, losing their membrane integrity and releasing damage-associated molecular patterns (DAMPs) into their environment (10).”
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Authors: Komori, T.
Affiliations: Nagasaki University (JP)
Corresponding author: Komori, Toshihisa
ORCID: Komori, Toshihisa
Venue: International Journal of Molecular Sciences
Publisher: MDPI AG
Published: 2016-12-06
Volume: 17
Issue: 12
Pages: 2045
ISSN: 1422-0067 (ISSN-L)
DOI: 10.3390/ijms17122045
PMC: PMC5187845
OpenAlex: W2560057190
Cited by: 176
References: 128
Citations by year: 2026: 12 · 2025: 16 · 2024: 17 · 2023: 36 · 2022: 24 · 2021: 19 · 2020: 21 · 2019: 9 · 2018: 14 · 2017: 8
FWCI: 0.93
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: International Journal of Molecular Sciences (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Japanese Ministry of Education, Culture, Sports, Science and Technology, Japan (26221310)
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 › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords: cell death, chondrocytes, osteoblasts, osteocytes, apoptosis, osteoarthritis, osteoporosis, endochondral ossification, p53, retinoblastoma protein, osteosarcoma, post-traumatic osteoarthritis, damage-associated molecular patterns, Bcl-xL, RANKL, osteoclastogenesis, pannexin-1 channels, ATP release, skeletal development, bone preservation
MeSH terms: Alarmins, Animals, Humans, Osteoblasts, Osteocytes, Apoptosis, Chondrocytes

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Cell Death in Chondrocytes, Osteoblasts, and Osteocytes

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