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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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“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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“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]
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Gut–X Axis and Its Role in Poultry Bone Health: A Review
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“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
“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 19
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
“(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
“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 22
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
“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
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
“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
“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 22
“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
“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
“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
“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
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
“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
“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
“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
“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
“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
“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
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 15
“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
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
Guo, L., Hao, R., Tian, F., An, N., & Wang, K. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.11.035 · Cited by 14
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
“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
“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
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
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
“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 9
“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
Ungsudechachai, T., Jittikoon, J., Honsawek, S., & Udomsinprasert, W. (2024) · Clinical and Translational Science · doi:10.1111/cts.13881 · Cited by 10
“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 12
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
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
Metadata
- 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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