Cell Death in Chondrocytes, Osteoblasts, and Osteocytes
Open accessAbstract
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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In vivo, osteocyte apoptosis is fundamental for initiating bone remodeling, independent of the stimulus causing osteocyte death such as estrogen loss, fatigue, or unloading.
“In vivo, osteocyte apoptosis is fundamental for initiating bone remodeling,61 independent of the stimulus causing osteocyte death such as estrogen loss,62 fatigue,63 or unloading.64”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [61]
Necrotic osteocytes release damage-associated molecular pattern (DAMP) proteins after the cell membrane is disrupted.
“Necrotic osteocytes release damage-associated molecular pattern (DAMP) proteins after the cell membrane is disrupted.61”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [61]
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BackgroundFoxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis
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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 · see citing works
Murine Gcm1 gene is expressed in a subset of placental trophoblast cells
Basyuk, E. I., Cross, J. C., Corbin, J., Nakayama, H., Hunter, P., Nait‐Oumesmar, B., & Lazzarini, R. A. (1999) · Developmental Dynamics · doi:10.1002/(sici)1097-0177(199904)214:4 · Cited by 148 · see citing works
Self-citationHirschmann-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 · see citing works
Cell signals transduced by complement
Bohana‐Kashtan, O. (2004) · Molecular Immunology · doi:10.1016/j.molimm.2004.04.007 · Cited by 145 · cited 1× · see citing works
“Complement may be activated by DAMPs, and activated complement components may induce chondrocyte death [62,63].”
BackgroundTGFβ 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× · see citing works
“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].”
BackgroundGagarina, 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 · see citing works
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 · see citing works
Glucocorticoid Signaling and Bone Biology
Komori, T. (2016) · Hormone and Metabolic Research · doi:10.1055/s-0042-110571 · Cited by 126 · cited 2× · see citing works
“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-citationUehara, 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× · see citing works
“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).”
BackgroundKurz, 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 · see citing works
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 · see citing works
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 · see citing works
Zhu, L., Zhu, L., Xie, E., & Chang, L. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.7.3552 · Cited by 112 · see citing works
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 110 · cited 1× · see citing works
“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…”
BackgroundFunctions 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 110 · cited 13× · see citing works
“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-citationIncreased 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 · see citing works
Carlo, M. D., & Loeser, R. F. (2008) · Current Rheumatology Reports · doi:10.1007/s11926-008-0007-8 · Cited by 106 · cited 4× · see citing works
“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).”
BackgroundInfluentialMoriishi, 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× · see citing works
“In BCl2 transgenic mice, osteocyte death does not induce bone resorption because the extracellular communication system is also disrupted [120].”
BackgroundSelf-citationBuckley, 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 97 · see citing works
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× · see citing works
“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].”
BackgroundResultLi, 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 · see citing works
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× · see citing works
“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.”
BackgroundInfluentialFOXO1 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 · see citing works
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 · see citing works
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 · see citing works
Self-citationCalbó, 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 86 · see citing works
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× · see citing works
“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].”
BackgroundStanislaus, 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 · see citing works
Mueller, A., Odze, R. D., Jenkins, T. D., Shahsesfaei, A., Nakagawa, H., Inomoto, T., & Rustgi, A. K. (1997) · PubMed · Cited by 70 · see citing works
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× · see citing works
“Furthermore, a significant decrease has been reported in chondrocyte numbers in articular cartilage with aging [39,44,45].”
BackgroundRossi, 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× · see citing works
“Rb family proteins play an important role in chondrocyte proliferation and differentiation [19,20].”
BackgroundMoriishi, 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× · see citing works
“Osteoblastogenesis in BCL2-overexpressing primary osteoblasts in vitro is also controversial, and was previously reported to be enhanced and inhibited [81].”
BackgroundInfluentialSelf-citationEstrogen 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 · see citing works
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 58 · cited 2× · see citing works
“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].”
BackgroundResultChondrocyte 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 · see citing works
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× · see citing works
“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].”
BackgroundResultLemaire, I. B., Falzoni, S., Zhang, B., Pellegatti, P., & Virgilio, F. D. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002780 · Cited by 53 · see citing works
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 · see citing works
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× · see citing works
“The inhibition of osteoblast proliferation in Bcl2−/− mice is, at least in part, due to the up-regulation of p53 and FoxOs [80].”
BackgroundResultInfluentialSelf-citationBCL2 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× · see citing works
“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].”
BackgroundImpaired 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 · see citing works
Self-citationATP P2 receptors and regulation of bone effector cells.
Gallagher, J. A. (2004) · PubMed · Cited by 41 · see citing works
Burkhart, D. L., Wirt, S. E., Zmoos, A., Kareta, M. S., & Sage, J. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001003 · Cited by 36 · see citing works
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× · see citing works
“Similar to osteocytes, autophagy also protects chondrocytes from apoptosis, and its failure leads to apoptosis [35,36].”
BackgroundImai, K., & Senoo, H. (1998) · The Anatomical Record · doi:10.1002/(sici)1097-0185(199804)250:4 · Cited by 34 · see citing works
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× · see citing works
“The intra-articular administration of caspase inhibitors has been shown to inhibit chondrocyte death and cartilage degradation in OA rabbit models [46,47].”
BackgroundMoriishi, 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× · see citing works
“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-citationRevisiting 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× · see citing works
“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].”
BackgroundIto, 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× · see citing works
“Rb is highly phosphorylated, while unphosphorylated p107 levels are elevated in Cdk6/Cyclin D1 double transgenic mice [21].”
BackgroundInfluentialSelf-citationHerzog, 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 · see citing works
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 · see citing works
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× · see citing works
“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-citationLoss 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× · see citing works
“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 · see citing works
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Molecular mechanosensors in osteocytes
Qin, L., Liu, W., Cao, H., & Xiao, G. (2020) · Bone Research · doi:10.1038/s41413-020-0099-y · Cited by 484 · see citing works
“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…”
BackgroundBone 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 · see citing works
“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.”
BackgroundThe 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 353 · see citing works
“OA is a degenerative disease associated with articular cartilage damage, osteophyte formation, and hardening of the subchondral bone [152,153].”
BackgroundRegulation 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 265 · see citing works
“p53 and FoxOs have similar functions in inhibiting cell cycles and inducing cell death in osteoblasts [141].”
BackgroundOsteocyte 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 · see citing works
“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).”
BackgroundCell death regulation: A new way for natural products to treat osteoporosis
Li, Z., Li, D., Chen, R., Gao, S., Xu, Z., & Li, N. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106635 · Cited by 180 · see citing works
The role of TGF-beta3 in cartilage development and osteoarthritis
Du, X., Cai, L., Xie, J., & Zhou, X. (2023) · Bone Research · doi:10.1038/s41413-022-00239-4 · Cited by 165 · see citing works
“Chondrocyte death Dynamic and accurate regulation of cell death in chondrocytes is pivotal in skeletal development, maintenance, and repair as well as in the pathological course of OA and osteoporosis (OP).(132,133) Different types of cell death in cartilage have been reported, including three types of physiological/p…”
BackgroundExercise for osteoporosis: A literature review of pathology and mechanism
Zhang, L., Zheng, Y.-L., Wang, R., Wang, X., & Zhang, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1005665 · Cited by 152 · see citing works
“Hughes et al. (13) reported that 17b-estradiol increased the apoptosis rate of rat OCs from 0.5% to 2.7%, and estrogen deficiency prolonged the survival period of OCs, increasing the number of cells by 2–3 times, and leading to enlargement of the bone absorption cavity.”
BackgroundInfluentialRunx2 is essential for the transdifferentiation of chondrocytes into osteoblasts
Qin, X., Jiang, Q., Nagano, K., Moriishi, T., Miyazaki, T., Komori, H., Ito, K., von der Mark, K., Sakane, C., Kaneko, H., et al. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1009169 · Cited by 126 · see citing works
“…apoptosis of terminal hypertrophic chondrocytes in Runx2 fl/flCre mice may have promoted the vascular invasion into the cartilage because apoptotic terminal hypertrophic chondrocytes may finally die by necrosis without phagocytosis and release DAMPs, which induce osteoclastogenesis [23, 31].”
Self-citationThe roles of osteocytes in alveolar bone destruction in periodontitis
Huang, X., Xie, M.-R., Xie, Y.-L., Mei, F., Lu, X., Li, X.-S., & Chen, L.-L. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02664-7 · Cited by 110 · see citing works
“Apoptotic osteocytes can also release adenosine triphosphate (ATP) through activated pannexin 1 channels, and ATP acts on osteocytes, osteoblasts, osteoclasts and macrophages via ATP receptor-gated (P2) channels and consequently induces enhanced production of RANKL in bystander osteocytes and osteoblasts, aggregation…”
BackgroundCorrado, A., Cici, D., Rotondo, C., Maruotti, N., & Cantatore, F. P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103679 · Cited by 101 · see citing works
“The increase in osteoblast apoptosis has been proposed among the mechanisms of the reduced bone-forming capacity of senescent bone [75].”
BackgroundScaffold-Based Tissue Engineering Strategies for Osteochondral Repair
Fu, J.-N., Wang, X., Yang, M., Chen, Y., Zhang, J., Deng, R., Zhang, Z., Yu, J., & Yuan, F. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.812383 · Cited by 96 · see citing works
Zhang, S., Xu, J., Si, H., Wu, Y., Zhou, S., & Shen, B. (2022) · Antioxidants · doi:10.3390/antiox11091668 · Cited by 84 · see citing works
“Reactive oxygen species (ROS) production and subsequent lipid peroxidation are related to the antioxidant capacity of chondrocytes, playing key roles in cartilage degradation and chondrocyte death [5,6].”
BackgroundRiegger, J., & Brenner, R. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051560 · Cited by 73 · see citing works
Osteoprotective Roles of Green Tea Catechins
Huang, H., Cheng, T., Lin, S., Ho, C.-J., Chyu, J., Yang, R., Chen, C., & Shen, C. (2020) · Antioxidants · doi:10.3390/antiox9111136 · Cited by 70 · see citing works
“In addition, the increase in osteoblast apoptosis is a possible mechanism for the reduced bone-forming ability of senescent bone [18].”
BackgroundZhang, H., Wang, A., Li, G., Zhai, Q., Huang, Z., Wang, X., Cao, Z., Liu, L., Liu, G., Chen, B., et al. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.01.026 · Cited by 69 · see citing works
ECM signaling in cartilage development and endochondral ossification
Prein, C., & Beier, F. (2018) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2018.11.003 · Cited by 68 · see citing works
IL-33/IL-31 Axis in Osteoporosis
Martinis, M. D., Sirufo, M. M., Suppa, M., & Ginaldi, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041239 · Cited by 68 · see citing works
“Release of alarmins or DAMPs (danger-associated molecular patterns), including IL-33, from damaged cells is a relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases, cancer and osteoporosis [89,90].”
BackgroundDNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis
Ruan, B., Dong, J. P., Wei, F., Huang, Z., Yang, B., Zhang, L., Li, C., Dong, H., Cao, W., Wang, H., et al. (2024) · Bone Research · doi:10.1038/s41413-024-00365-1 · Cited by 66 · see citing works
“8,9 Although past researches have established that various forms of regulated cell death, such as apoptosis, 10 autophagic cell death, 11 pyroptosis, 12 necroptosis.”
Xu, T., Chen, P., Zhang, C., Shaukat, A., Lin, L., Yue, K., Ding, W., Tong, X., Liu, K., He, Y., et al. (2023) · npj Biofilms and Microbiomes · doi:10.1038/s41522-022-00360-6 · Cited by 67 · see citing works
Emerging roles of long noncoding RNA in chondrogenesis, osteogenesis, and osteoarthritis.
Sun, H., Peng, G., Ning, X., Wang, J., Yang, H., & Deng, J. (2019) · Europe PMC (PubMed Central) · Cited by 63 · see citing works
Chondrocyte death involvement in osteoarthritis
Salucci, S., Falcieri, E., & Battistelli, M. (2022) · Cell and Tissue Research · doi:10.1007/s00441-022-03639-4 · Cited by 63 · see citing works
“Necrosis is a pathological and non-programmed form of cell death, caspase- and energy-independent (Zhang et al. 2018; Komori 2016; Martin and Henry 2013).”
BackgroundAguirre, J. I., Castillo, E. J., & Kimmel, D. B. (2021) · Bone · doi:10.1016/j.bone.2021.116168 · Cited by 60 · see citing works
“The accumulated necrotic osteocytes generate an accrued amount of DAMPs that further stimulate inflammation.”
BackgroundInfluentialGuided Bone Regeneration Using Barrier Membrane in Dental Applications
Kim, K., Su, Y., Kucine, A. J., Cheng, K., & Zhu, D. (2023) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.3c00690 · Cited by 61 · see citing works
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“Osteoblast apoptosis increases with age (Komori, 2016; Tower, 2015) and is responsible for reduction in osteoblast number and activity, which contribute to decreased bone formation (Jilka & O’Brien, 2016; Jilka, Weinstein, Parfitt & Manolagas, 2007; Weinstein & Manolagas, 2000).”
BackgroundIcariin: A Potential Molecule for Treatment of Knee Osteoarthritis
Zhang, J., Fan, F., Liu, A., Zhang, C., Li, Q., Zhang, C., He, F., & Shang, M. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.811808 · Cited by 53 · see citing works
“Degradation of the extracellular matrix promotes chondrocyte apoptosis at the same time (Komori 2016).”
BackgroundOsteoimmunology in Periodontitis: Local Proteins and Compounds to Alleviate Periodontitis
Sirisereephap, K., Maekawa, T., Tamura, H., Hiyoshi, T., Domon, H., Isono, T., Terao, Y., Maeda, T., & Tabeta, K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105540 · Cited by 56 · see citing works
Ferroptosis Plays a Role in Human Chondrocyte of Osteoarthritis Induced by IL-1β In Vitro
Xu, W., Zhang, B., Xi, C., Qin, Y., Lin, X., Wang, B., Kong, P., & Yan, J. (2023) · Cartilage · doi:10.1177/19476035221142011 · Cited by 53 · see citing works
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“A large body of evidence suggests that the apoptosis of osteoblasts under pathological conditions leads to an imbalance in bone formation–resorption, which is closely associated with the development of OP (Komori, 2016; Chen et al., 2018).”
BackgroundTargeting Regulated Chondrocyte Death in Osteoarthritis Therapy.
Zhu, R., Wang, Y., Ouyang, Z.-W., Hao, W., Zhou, F., Lin, Y., Cheng, Y., Zhou, R.-P., & Hu, W. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115707 · Cited by 50 · see citing works
Geniposide ameliorates glucocorticoid-induced osteoblast apoptosis by activating autophagy
Huang, J., Ye, Y., Xiao, Y., Ren, Q., Zhou, Q., Zhong, M., Jiao, L., & Wu, L. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113829 · Cited by 47 · see citing works
McCutcheon, S., Majeska, R. J., Spray, D. C., Schaffler, M. B., & Vázquez, M. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3954 · Cited by 46 · see citing works
“In the current studies we found that acute ATP exposure turned on osteocyte RANKL expression, consistent with previous studies showing that ATP can stimulate RANKL expression.((40,41)) We further discovered that with osteocyte apoptosis, ATP was the essential signal driving the increase in bystander osteocyte RANKL ex…”
ResultZheng, L., Pi, C., Zhang, J., Fan, Y., Cui, C., Zhou, Y., Sun, J., Yuan, Q., Xu, X., Ye, L., et al. (2018) · Bone Research · doi:10.1038/s41413-018-0027-6 · Cited by 46 · see citing works
“Articular chondrocytes exhibited an agerelated decline in proliferation and synthetic capacity.(46) As age increased, the calcified cartilage layer became thicker.”
BackgroundFabrication of chondroitin sulfate calcium complex and its chondrocyte proliferation in vitro
Shen, Q., Zhang, C., Mo, H., Zhang, H., Qin, X., Li, J., Zhang, Z., & Richel, A. (2020) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2020.117282 · Cited by 45 · see citing works
LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice
Lei, Y., Fu, X., Li, P., Lin, S., Yan, Q., Lai, Y., Liu, X., Wang, Y., Bai, X., Liu, C.-J., et al. (2020) · Bone Research · doi:10.1038/s41413-020-00108-y · Cited by 45 · see citing works
“In the absence of Pinch, TGF-β/Smad2/3 signaling is impaired due to reduced expression and activation and accelerated degradation of Smad2/3, which reduces chondrocyte proliferation and survival and upregulates Runx2.”
BackgroundInfluentialCao, S., Wei, Y., Xu, H., Weng, J., Qi, T., Yu, F., Liu, S., Xiong, A., Liu, P., & Zeng, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1202436 · Cited by 39 · see citing works
Non-bone metastatic cancers promote osteocyte-induced bone destruction
Pin, F., Prideaux, M., Huot, J. R., Essex, A. L., Plotkin, L. I., Bonetto, A., & Bonewald, L. F. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.06.030 · Cited by 36 · see citing works
Zhang, W., Zhong, B., Zhang, C., Luo, C., & Zhan, Y. (2017) · FEBS Open Bio · doi:10.1002/2211-5463.12345 · Cited by 35 · see citing works
Li, L., Wei, X., Wang, D., Lv, Z., Geng, X., Li, P., Lu, J., Wang, K., Wang, X., Sun, J. M., et al. (2020) · Arthritis & Rheumatology · doi:10.1002/art.41230 · Cited by 34 · see citing works
“Decreases in chondrocytes and in the cartilage proliferative capacity contribute to the degradation of the age- related OA cartilage matrix (2,3).”
BackgroundLymphatic platelet thrombosis limits bone repair by precluding lymphatic transporting DAMPs
Zheng, Y., Cong, L., Zhao, L., Wang, P., Xing, L., Liu, J., Xu, H., Li, N., Zhao, Y., Yuan, L., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56147-8 · Cited by 32 · see citing works
“Pro-in fl ammatory factors (TNF-α , IL-1, and IL-6) and growth factors (TGF β 1 and PDGF) are vitalligands of OB apoptosis and BMSC proliferation 20,33 .”
Roper, P., Shao, C., & Veis, D. (2020) · Cells · doi:10.3390/cells9102157 · Cited by 30 · see citing works
“Other DAMPs, such as S100 proteins and high-mobility group box 1 (HMGB1), likely activate other PRRs and contribute additional osteolytic stimuli [67].”
BackgroundFTO-mediated m6A demethylation of pri-miR-3591 alleviates osteoarthritis progression
Liu, W., Jiang, T., Zheng, W., Zhang, J., Li, A., Lu, C., & Lin, Z. (2023) · Arthritis Research & Therapy · doi:10.1186/s13075-023-03035-5 · Cited by 31 · see citing works
Osteocytes: Their Lacunocanalicular Structure and Mechanoresponses
Moriishi, T., & Komori, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084373 · Cited by 31 · see citing works
“Thus, osteocyte ablation by diphtheria toxin enhanced bone resorption and inhibited bone formation [29,35] (Figures 2 and 4).”
BackgroundSelf-citationHu, H., Zhang, Z.-Y., Luo, Z. X., Ti, H., Wu, J., Nie, H., Yuan, Z., Wu, X. L., Zhang, K.-Y., Shi, S., et al. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02633-3 · Cited by 31 · see citing works
“The process of cell death within skeletal component cells is crucial for bone development, maintenance, repair, and overall functional integrity [12].”
Comparison of Necroptosis With Apoptosis for OVX-Induced Osteoporosis
He, B., Zhu, Y., Cui, H., Sun, B., Su, T., & Wen, P. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.790613 · Cited by 29 · see citing works
“These stimulate the generation of multiple immunostimulatory cytokines and proinflammatory molecules, the aggregation and energization of immune cells (e.g., macrophages, monocytes, and neutrophils), which also induce the secretion of RANKL and bone resorption (Komori, 2013; Komori, 2016).”
BackgroundJia, L., Ma, T., Lv, L., Yu, Y., Zhao, M., Chen, H., & Gao, L. (2023) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.114517 · Cited by 29 · see citing works
Zhao, X., Wang, T., Cai, B., Wang, X., Feng, W. S., Han, Y., Li, D., Li, S., & Liu, J. (2019) · PubMed Central · Cited by 29 · see citing works
The role of the complement system in disc degeneration and Modic changes
Heggli, I., Teixeira, G. Q., Iatridis, J. C., Neidlinger‐Wilke, C., & Dudli, S. (2024) · JOR Spine · doi:10.1002/jsp2.1312 · Cited by 28 · see citing works
“85 While under physiological conditions tissue damage-mediated complement system activation helps to clear dying cells and remove immune complexes /pathogens, persistent and accumulating cell damage can exceed homeostatic activation and amplify rather than suppress pro-inflammatory processes.”
BackgroundXue, J., Ye, J., Xia, Z., & Cheng, B. (2019) · Cellular and Molecular Biology · doi:10.14715/cmb/2019.65.6.15 · Cited by 28 · see citing works
From death to birth: how osteocyte death promotes osteoclast formation
Zhao, W., Qian, J., Li, J., Su, T., Deng, X., Fu, Y., Liang, X., & Cui, H. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1551542 · Cited by 26 · see citing works
“…to PRRs, such as TLR2, TLR4, and RAGE, on immune cells including macrophages and dendritic cells, and promote their production of pro-in fl ammatory cytokines, such as TNF-a and IL-6, which further induces RANKL expression in osteoblast lineage cells or promotes osteoclastogenesis directly (91).”
Ubiquitin‐specific peptidases: Players in bone metabolism
Shen, J., Lin, X., Dai, F., Chen, G., Lin, H., Fang, B., & Liu, H. (2023) · Cell Proliferation · doi:10.1111/cpr.13444 · Cited by 27 · see citing works
Ay, B., Parolia, K., Liddell, R. S., Qiu, Y., Grasselli, G., Cooper, D. M. L., & Davies, J. E. (2020) · Communications Biology · doi:10.1038/s42003-019-0747-1 · Cited by 27 · see citing works
Takemura, Y., Moriyama, Y., Ayukawa, Y., Kurata, K., Rakhmatia, Y. D., & Koyano, K. (2018) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36597 · Cited by 26 · see citing works
Single‐Cell RNA ‐Sequencing Reveals the Breadth of Osteoblast Heterogeneity
Yoshioka, H., Okita, S., Nakano, M., Minamizaki, T., Nubukiyo, A., Sotomaru, Y., Bonnelye, E., Kozai, K., Tanimoto, K., Aubin, J. E., et al. (2021) · JBMR Plus · doi:10.1002/jbm4.10496 · Cited by 25 · see citing works
“Indeed, apoptotic response promotes osteoblast differentiation via the p53-Akt-FoxO pathway.((51)) Thus, expression of apoptotic versus survival signals and, concomitantly, apoptotic behavior may differ among individual osteoblasts, contributing to noise in the expression profiles and to our inability to recognize a d…”
BackgroundBi, H., Wang, D., Liu, X., Wang, G., & Wu, X. (2020) · Journal of Biosciences · doi:10.1007/s12038-020-0024-y · Cited by 25 · see citing works
“Osteoblasts, one of the major bone-forming cells, have been identified as a pivotal regulator in skeletal development, maintenance, and repair as well as bone microenvironment homeostasis (Komori 2016; Long 2011).”
BackgroundRösch, G., Zaucke, F., & Jenei‐Lanzl, Z. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00039.2023 · Cited by 25 · see citing works
Qu, X., Mei, J., Yu, Z., Zhai, Z., Qiao, H., & Dai, K. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.05.035 · Cited by 25 · see citing works
Wei, Y., & Sun, Y. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1117-8_12 · Cited by 25 · see citing works
PGC-1α in osteoarthritic chondrocytes: From mechanism to target of action
Wang, H., Su, J., Yu, M., Xia, Y., & Wei, Y. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1169019 · Cited by 24 · see citing works
“Apoptosis is an important process in the occurrence and development of OA, and the death of chondrocytes caused by apoptosis is positively correlated with the severity of OA (Komori, 2016).”
BackgroundSong, W., Zhang, Y., Wang, J., Ma, T., Hao, L., & Wang, K. (2018) · Cytokine · doi:10.1016/j.cyto.2017.12.021 · Cited by 23 · see citing works
Human skeletal physiology and factors affecting its modeling and remodeling
Nandiraju, D., & Ahmed, I. (2019) · Fertility and Sterility · doi:10.1016/j.fertnstert.2019.10.005 · Cited by 22 · see citing works
Promising diagnostic and therapeutic circRNAs for skeletal and chondral disorders
Chen, G., Tang, W., Wang, S., Long, C., He, X., Yang, D., & Peng, S. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.57887 · Cited by 22 · see citing works
“As a result, hypertrophic chondrocytes attempt to repair eroded cartilage, but in turn release more matrix degradation products and proinflammatory factors, which then leads to structural alterations in articular cartilage, subchondral bone, synovium, capsule, ligaments, and periarticular muscles [42-44].”
BackgroundJia, C., Li, X., Pan, J., Ma, H., Wu, D., Lü, H., Wang, W., Zhang, X., & Yi, X. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/1135827 · Cited by 22 · see citing works
“OA is a degenerative disease associated with age and involves numerous factors in its pathophysiology, which include imbalance in ECM metabolism, in fl ammation, and apoptosis [41, 42].”
Gut–X Axis and Its Role in Poultry Bone Health: A Review
Yanan, L., Yue, T.-J., Ding, W., Xu, B., Li, J., & Huang, S. (2025) · Microorganisms · doi:10.3390/microorganisms13040757 · Cited by 22 · see citing works
“The prevalence of bone development issues related to TD in broiler chickens has resulted in substantial economic losses, estimated at approximately USD 150 million in the United States [6].”
The inhibitory roles of Ihh downregulation on chondrocyte growth and differentiation
Deng, A., Zhang, H., Hu, M., Liu, S., Wang, Y., Gao, Q., & Guo, C. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.5458 · Cited by 21 · see citing works
“Chondrocyte hypertrophy is required for endochondral bone formation; elongated chondrocytes exit the cell cycle to become prehypertrophic chondrocytes prior to terminally differentiating to form hypertrophic chondrocytes (2).”
BackgroundTNF-α promotes osteocyte necroptosis by upregulating TLR4 in postmenopausal osteoporosis
Cui, H., Li, J., Li, X., Su, T., Wen, P., Wang, C., Deng, X., Fu, Y., Zhao, W., Li, C., et al. (2024) · Bone · doi:10.1016/j.bone.2024.117050 · Cited by 20 · see citing works
Xu, Z., Xu, J., Li, S., Cui, H., Zhang, G., Ni, X., & Wang, J. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.986192 · Cited by 20 · see citing works
“(10) and inhibits osteoblast apoptosis, thereby promoting osteoblastic growth (11).”
BackgroundAmeliorative effect of naringin against thiram-induced tibial dyschondroplasia in broiler chicken
Jiang, X., Li, J., Wang, Y., Iqbal, M., Waqas, M., Yang, H., Li, Z., Mehmood, K., Qamar, H., & Li, J. (2020) · Environmental Science and Pollution Research · doi:10.1007/s11356-020-07732-5 · Cited by 20 · see citing works
“Endochondral osteogenesis is a complex process, which is closely related to chondrocytes, osteoblasts, and blood vessel differentiation and regulated by multiple hormones and cytokines (Lee et al. 1996; Komori 2016).”
BackgroundWang, J., Xin, Y., Dong, Z., Li, S., & Yang, G. (2025) · Experimental Gerontology · doi:10.1016/j.exger.2025.112974 · Cited by 21 · see citing works
Guo, X., Pan, X., Wu, J., Li, Y., & Nie, N. (2022) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-022-00694-7 · Cited by 19 · see citing works
“The death of chondrocyte contributes to cartilage degradation in OA (Komori 2016).”
BackgroundChloride Channel and Inflammation-Mediated Pathogenesis of Osteoarthritis
Lin, Z., Deng, Z., Liu, J., Lin, Z., Chen, S., Deng, Z., & Li, W. (2022) · Journal of Inflammation Research · doi:10.2147/jir.s350432 · Cited by 18 · see citing works
Ye, T., Cao, P., Jin, Q., Zhou, Q., Rao, D. S., & Qiu, S. (2017) · PLoS ONE · doi:10.1371/journal.pone.0186012 · Cited by 17 · see citing works
“Apoptosing osteocytes may release ATP as a “find me” signal to stimulate RANKL expression in the neighboring viable osteocytes, which enhances osteoclast number and activity on the bone surface [20, 21].”
BackgroundMyoneurin regulates BMP signaling by competing with Ppm1a for Smad binding
Yang, S., Ning, G., Hou, Y., Cao, Y., Xu, J., Wu, J., Zhang, T., & Wang, Q. (2022) · iScience · doi:10.1016/j.isci.2022.104495 · Cited by 17 · see citing works
“It is well known that the tumor suppressor p53 plays a primary role in inducing apoptosis in many cell types, including chondrocytes (Ito et al., 2014; Komori, 2016; Ning et al., 2013; Vogelstein and Kinzler, 1992).”
BackgroundRoles of Sp7 in osteoblasts for the proliferation, differentiation, and osteocyte process formation
Jiang, Q., Nagano, K., Moriishi, T., Komori, H., Sakane, C., Matsuo, Y., Zhang, Z., Nishimura, R., Ito, K., Qin, X., et al. (2024) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2024.06.005 · Cited by 17 · see citing works
“Inflammatory molecules, including damage-associated molecular patterns, are released through the canaliculi to the bone surface and vascular canals in bone, leading to the production of proinflammatory cytokines that induce Tnfsf11 expression [16 – 18].”
BackgroundSelf-citationAntxr1, Which is a Target of Runx2, Regulates Chondrocyte Proliferation and Apoptosis
Jiang, Q., Qin, X., Yoshida, C. A., Komori, H., Yamana, K., Ohba, S., Hojo, H., Croix, B. S., Kawata-Matsuura, V. K. S., & Komori, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072425 · Cited by 17 · see citing works
“Spp1 expression in the chondrocytes surrounding TUNEL-positive cells may have been induced by danger-associated molecular patterns (DAMPs) released from the necrotic cells, which originated from apoptotic chondrocytes, because Spp1 expression is induced by inflammation [36,37].”
BackgroundSelf-citationWang, Q., Huang, P., Wu, J., Zhang, T.-Q., Li, L., Huang, L., Yu, Y., Wang, M., & He, J. (2022) · Environmental Toxicology · doi:10.1002/tox.23627 · Cited by 17 · see citing works
“Cell death is one of the mechanisms that promote the onset and progression of osteoarthritis.(16) Pyroptosis and apoptosis are the two main ways of cell death.”
BackgroundYan, T.-B., Li, C., Jiao, G., Wu, W., & Liu, H. (2018) · Free Radical Research · doi:10.1080/10715762.2017.1423070 · Cited by 17 · see citing works
“Osteoblast apoptosis was considered to be a critical event in the pathogenesis of osteoporosis [4].”
BackgroundLi, W., Liu, Y., Wei, M., Yang, Z., Li, Z., Guo, Z., Yan, L. W., Yang, L., Tang, H., Li, B., et al. (2025) · Advanced Science · doi:10.1002/advs.202504768 · Cited by 16 · see citing works
Park, J., Koh, E.-B., Seo, Y.-J., Oh, H.-S., & Byun, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015252 · Cited by 16 · see citing works
“As such, although p53 inhibits osteoblast proliferation and promotes osteoblast apoptosis to reduce bone formation, it also positively affects osteoblast differentiation through the Akt-FoxOs pathway [23].”
BackgroundDong, J. P., Ruan, B., Zhang, L., Wei, A., Li, C., Tang, N., Zhu, L., Jiang, Q. Y., & Cao, W. (2024) · Research · doi:10.34133/research.0457 · Cited by 16 · see citing works
“PPO induced by metal wear particles is known to be promoted by various types of regulated bone cell death, including necroptosis, apoptosis, pyroptosis, or ferroptosis [10,11].”
BackgroundDeng, Z., Lin, Z., Zhong, Q., Lu, M.-Q., Fang, H., Liu, J., Duan, L., Chen, L., Wang, L., Wang, D., et al. (2021) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmab010 · Cited by 16 · see citing works
“This may be one of the main forms of chondrocyte death during OA [4,5].”
BackgroundChen, R., Ye, B., Xie, H., Huang, Y., Wu, Z., Wu, H., Wang, X., Miao, H., & Liang, W. (2020) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-020-02070-1 · Cited by 16 · see citing works
“chondrocyte apoptosis is definitely correlated with cartilage degeneration in OA [6, 7].”
BackgroundCao, S., Wei, Y., Yue, Y., Xiong, A., & Zeng, H. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s462722 · Cited by 15 · see citing works
“Despite numerous reviews delving into PCD’s role in OA, 4,10,12,25,27,34,35 there remains a gap in visualized analyses and comprehensive summaries delineating developmental trends, primary contributors, and core research priorities.”
BackgroundEnhanced cortical bone expansion in Lgals3-deficient mice during aging
Maupin, K. A., Weaver, K., Bergsma, A. L., Christie, C. M., Zhong, Z. A., Yang, T., & Williams, B. O. (2018) · Bone Research · doi:10.1038/s41413-017-0003-6 · Cited by 15 · see citing works
“During normal bone remodeling, osteoclast precursors from the myeloid lineage are recruited to areas of old or damaged bone primarily by signals from fully mature osteoblasts, known as osteocytes, which sense changes in bone matrix quality or in mechanical stress.(2,3) Osteoclast precursors fuse and form a mature oste…”
BackgroundLiu, Y., Pu, X., Duan, M., Chen, C., Zhao, Y., Zhang, D., & Xie, J. (2023) · Nano Letters · doi:10.1021/acs.nanolett.3c01739 · Cited by 14 · see citing works
The Emerging Role of the Mitochondrial Respiratory Chain in Skeletal Aging
Tao, H., Zhu, P., Xia, W., Chu, M., Chen, K., Wang, Q., Gu, Y., Lu, X., Bai, J., & Geng, D. (2023) · Aging and Disease · doi:10.14336/ad.2023.0924 · Cited by 14 · see citing works
“Osteoblasts with typical apoptotic features are not commonly found in vivo , but can be found in fracture calluses and at the anterior end of sutures of the developing mouse skull [193, 194].”
BackgroundMoriishi, T., Ito, T., Fukuyama, R., Qin, X., Komori, H., Kaneko, H., Matsuo, Y., Yoshida, N., & Komori, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063173 · Cited by 14 · see citing works
Self-citationWang, W., Wang, D., Li, X., Ai, W., Wang, X., & Wang, H. (2022) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2022.158040 · Cited by 14 · see citing works
Guo, L., Hao, R., Tian, F., An, N., & Wang, K. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.11.035 · Cited by 14 · see citing works
Abdulrahman, S. J., Abdulhadi, M. A., Jalil, A. T., Falah, D., Merza, M. S., Almulla, A. F., Ali, A., & Ali, R. T. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08839-x · Cited by 12 · see citing works
“Osteoblasts [15], osteoclasts [16], osteocytes [15], and bone lining cells are the fundamental cells of bones.”
BackgroundATP transporters in the joints
Larranaga‐Vera, A., Marco-Bonilla, M., Largo, R., Herrero‐Beaumont, G., Mediero, A., & Cronstein, B. N. (2021) · Purinergic Signalling · doi:10.1007/s11302-021-09810-w · Cited by 12 · see citing works
“Moreover, this could be related to the way that (as shown in other cell types) hypoxia regulates Cx43 dephosphorylation, translocation, and proteosomal degradation [69].”
BackgroundFu, S., Yan, M., Fan, Q., & Xu, J. (2022) · Tissue and Cell · doi:10.1016/j.tice.2022.101917 · Cited by 12 · see citing works
Nanoengineered Endocytic Biomaterials for Stem Cell Therapy
Wang, Y., Sun, C., Liu, Z., Zhang, S., Gao, K., Yi, F., Zhou, W., & Liu, H. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202410714 · Cited by 11 · see citing works
Li, Y., Nie, J., Deng, C., & Li, H. (2023) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-023-03658-z · Cited by 10 · see citing works
“Discussion As the only cell type in cartilage tissue, chondrocytes express and secrete a large amount of extracellular matrix (ECM) to maintain the normal function of cartilage [31].”
BackgroundJapanese medaka Olpax6.1 mutant as a potential model for spondylo-ocular syndrome
Pan, Q., Lu, K., Luo, J., Jiang, Y., Xia, B., Chen, L., Wang, M., Ronggui, D. A. I., & Chen, T. (2023) · Functional & Integrative Genomics · doi:10.1007/s10142-023-01090-4 · Cited by 10 · see citing works
“Moreover, there is growing evidence that activation of the p53 signaling pathway promotes apoptosis in osteoblasts (Komori 2016; Zheng et al.”
BackgroundZhang, Z., Wu, W., Li, M., Du, L., Li, J., Yin, X., & Zhang, W. (2024) · Nano Today · doi:10.1016/j.nantod.2024.102343 · Cited by 10 · see citing works
Ungsudechachai, T., Jittikoon, J., Honsawek, S., & Udomsinprasert, W. (2024) · Clinical and Translational Science · doi:10.1111/cts.13881 · Cited by 10 · see citing works
“30 Based on this premise, CLU is proposed to protect chondrocytes from inflammatory stress-induced apoptosis under oxidative stress conditions via activating the PI3K/Akt pathway.”
Ohori, F., Kitaura, H., Marahleh, A., Ma, J., Miura, M., Ren, J., Narita, K., Fan, Z., Lin, A., & Mizoguchi, I. (2025) · Scientific Reports · doi:10.1038/s41598-025-04697-8 · Cited by 10 · see citing works
Osteoclast: The novel whistleblower in osteonecrosis of the femoral head
Qi, M., Wang, Y., Yuan, T., Su, Y., Li, Z., & Sun, S. (2023) · Gene Reports · doi:10.1016/j.genrep.2023.101833 · Cited by 10 · see citing works
The unique function of p130Cas in regulating the bone metabolism
Jimi, E., Honda, H., & Nakamura, I. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107965 · Cited by 10 · see citing works
- 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)
- 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
- 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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