Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance
Various stressors such as ionizing radiation (IR), chemotherapeutic agents, oxidative stress, and inflammatory responses can trigger the stress-induced premature senescence (SIPS) of cells in the bone microenvironment, including osteocytes. However, little is known about the mechanisms underlying th...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/4/249 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850080301009600512 |
|---|---|
| author | Fanyu Zhao Haiqing Han Jing Wang Jianping Wang Jianglong Zhai Guoying Zhu |
| author_facet | Fanyu Zhao Haiqing Han Jing Wang Jianping Wang Jianglong Zhai Guoying Zhu |
| author_sort | Fanyu Zhao |
| collection | DOAJ |
| description | Various stressors such as ionizing radiation (IR), chemotherapeutic agents, oxidative stress, and inflammatory responses can trigger the stress-induced premature senescence (SIPS) of cells in the bone microenvironment, including osteocytes. However, little is known about the mechanisms underlying the senescent cellular regulation of the differentiation potential and bone homeostasis. Here, we report a secretory change in senescent osteocytes activated by IR, its subsequent impact on osteogenic and osteoclastic differentiation, and the inflammatory cascade response. It was observed that osteocytes exhibited altered biological function, persistent and incomplete DNA damage repair, and characteristic senescence phenotypes after exposure to IR in vitro. Meanwhile, a concomitant increase in the CC chemokine ligand 3 (CCL3), a key component of the senescence-associated secretory phenotype (SASP), was observed in the IR-induced senescent osteocytes, which could further downregulate the osteogenic differentiation and enhance the osteoclastic differentiation in cell supernatant co-culture experiments. Notably, the enhancement of the PI3K/Akt/NF-κB signaling pathway in IR-induced senescent osteocytes appears to be an essential driver of the imbalance between the osteogenic and osteoclastic differentiation potentials. Taken together, these data suggest a novel role of CCL3 in IR-induced bone homeostatic imbalance through SASP cascade secretion, mediated by the PI3K/Akt/NF-κB signaling pathway. |
| format | Article |
| id | doaj-art-7f999f40900b41acb1696554ab48c6e2 |
| institution | DOAJ |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-7f999f40900b41acb1696554ab48c6e22025-08-20T02:44:59ZengMDPI AGCells2073-44092025-02-0114424910.3390/cells14040249Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis ImbalanceFanyu Zhao0Haiqing Han1Jing Wang2Jianping Wang3Jianglong Zhai4Guoying Zhu5Institute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai 200032, ChinaInstitute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai 200032, ChinaInstitute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai 200032, ChinaInstitute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai 200032, ChinaInstitute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai 200032, ChinaInstitute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai 200032, ChinaVarious stressors such as ionizing radiation (IR), chemotherapeutic agents, oxidative stress, and inflammatory responses can trigger the stress-induced premature senescence (SIPS) of cells in the bone microenvironment, including osteocytes. However, little is known about the mechanisms underlying the senescent cellular regulation of the differentiation potential and bone homeostasis. Here, we report a secretory change in senescent osteocytes activated by IR, its subsequent impact on osteogenic and osteoclastic differentiation, and the inflammatory cascade response. It was observed that osteocytes exhibited altered biological function, persistent and incomplete DNA damage repair, and characteristic senescence phenotypes after exposure to IR in vitro. Meanwhile, a concomitant increase in the CC chemokine ligand 3 (CCL3), a key component of the senescence-associated secretory phenotype (SASP), was observed in the IR-induced senescent osteocytes, which could further downregulate the osteogenic differentiation and enhance the osteoclastic differentiation in cell supernatant co-culture experiments. Notably, the enhancement of the PI3K/Akt/NF-κB signaling pathway in IR-induced senescent osteocytes appears to be an essential driver of the imbalance between the osteogenic and osteoclastic differentiation potentials. Taken together, these data suggest a novel role of CCL3 in IR-induced bone homeostatic imbalance through SASP cascade secretion, mediated by the PI3K/Akt/NF-κB signaling pathway.https://www.mdpi.com/2073-4409/14/4/249CC chemokine ligand 3ionizing radiationinflammationosteocytescellular senescencePI3K/Akt/NF-κB signaling pathway |
| spellingShingle | Fanyu Zhao Haiqing Han Jing Wang Jianping Wang Jianglong Zhai Guoying Zhu Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance Cells CC chemokine ligand 3 ionizing radiation inflammation osteocytes cellular senescence PI3K/Akt/NF-κB signaling pathway |
| title | Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance |
| title_full | Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance |
| title_fullStr | Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance |
| title_full_unstemmed | Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance |
| title_short | Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance |
| title_sort | oversecretion of ccl3 by irradiation induced senescent osteocytes mediates bone homeostasis imbalance |
| topic | CC chemokine ligand 3 ionizing radiation inflammation osteocytes cellular senescence PI3K/Akt/NF-κB signaling pathway |
| url | https://www.mdpi.com/2073-4409/14/4/249 |
| work_keys_str_mv | AT fanyuzhao oversecretionofccl3byirradiationinducedsenescentosteocytesmediatesbonehomeostasisimbalance AT haiqinghan oversecretionofccl3byirradiationinducedsenescentosteocytesmediatesbonehomeostasisimbalance AT jingwang oversecretionofccl3byirradiationinducedsenescentosteocytesmediatesbonehomeostasisimbalance AT jianpingwang oversecretionofccl3byirradiationinducedsenescentosteocytesmediatesbonehomeostasisimbalance AT jianglongzhai oversecretionofccl3byirradiationinducedsenescentosteocytesmediatesbonehomeostasisimbalance AT guoyingzhu oversecretionofccl3byirradiationinducedsenescentosteocytesmediatesbonehomeostasisimbalance |