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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Simulated microgravity induces a time-dependent shift from autophagy to apoptosis in osteoblasts, validated by TSPO,
1Department of Orthopaedics, The Second Hospital of Lanzhou University, Lanzhou Gansu 730000, China.
Abstract:
Emerging evidence indicates that microgravity-induced osteoblast dysfunction is a critical contributor to spaceflight-associated bone loss. This study investigated the temporal dynamics of autophagy-apoptosis crosstalk in MC3T3-E1 osteoblasts under a rotary cell culture system (RCCS)-simulated microgravity. Crucially, time-course analysis (1, 3, 5, 10 days) revealed a biphasic autophagic response: initial enhancement of autophagic flux (LC3-II/Beclin-1 upregulation, p62 degradation) at day 3, exerting cytoprotective effects with reduced apoptosis, subsequently shifting to peak autophagy inhibition at day 5 concomitant with marked apoptosis activation (cleaved caspase-3 elevation) and mitochondrial dysfunction. By day 10, extensive cellular fragmentation dominated. Integrated proteomics identified TSPO, ATG12, and BNip3L as important mediators of this phenotypic switch. Murine hindlimb unloading experiments validated the upregulation of these proteins in bone tissue via Western blot and immunohistochemistry . We hypothesize that Early microgravity exposure triggers compensatory autophagy via ATG12-mediated vesicle expansion, whereas sustained stress is accompanied by TSOPO-associated ROS accumulation and BNip3L-linked alteration in autophagy-related pathways, contributing to apoptosis. Our finding suggests a biphasic temporal pattern in autophagy-apoptosis remodeling under simulated microgravity, highlighting potential time-sensitive windows for future therapeutic targets for spaceflight-associated osteopenia.
Insights
Spaceflight causes bone loss by affecting osteoblasts. This study reveals a biphasic response in cell death pathways, with early autophagy protection followed by later cell death, identifying potential therapeutic targets.
Area of Science:
- Space biology
- Cellular biology
- Biomedical research
Background:
- Spaceflight-associated bone loss is linked to osteoblast dysfunction.
- Understanding the cellular mechanisms of microgravity's effects on bone cells is crucial.
Purpose of the Study:
- To investigate the temporal dynamics of autophagy-apoptosis crosstalk in osteoblasts under simulated microgravity.
- To identify key molecular mediators of the cellular response to microgravity.
Main Methods:
- Utilized a rotary cell culture system (RCCS) to simulate microgravity.
- Performed time-course analysis of MC3T3-E1 osteoblasts over 10 days.
- Integrated proteomics and validated findings in murine hindlimb unloading models.
Main Results:
- Observed a biphasic autophagic response: initial enhancement (day 3) followed by inhibition (day 5).
- Early autophagy reduced apoptosis, while later stages showed increased apoptosis, mitochondrial dysfunction, and cellular fragmentation.
- Identified TSPO, ATG12, and BNip3L as key mediators in the switch between cytoprotection and cell death.
Conclusions:
- Simulated microgravity induces a time-dependent shift in autophagy-apoptosis pathways in osteoblasts.
- ATG12, TSPO, and BNip3L play critical roles in mediating this response.
- Findings suggest time-sensitive therapeutic windows for mitigating spaceflight-induced bone loss.
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