Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway
Zanyan Zhao1, Xiangpu Wang1, Yu Ma1
1State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
Abstract:
The microgravity conditions in outer space are widely acknowledged to induce significant bone loss. Recent studies have implicated the close relationship between Atp6v1h gene and bone loss. Despite this, the role of Atp6v1h in bone remodeling and its molecular mechanisms in microgravity have not been fully elucidated. To address this, we used a mouse tail suspension model to simulate microgravity. We categorized both wild-type and Atp6v1h knockout (Atp6v1h+/-) mice into two groups: regular feeding and tail-suspension feeding, ensuring uniform feeding conditions across all cohorts. Analysis via micro-CT scanning, hematoxylin-eosin staining, and tartrate-resistant acid phosphatase assays indicated that wild-type mice underwent bone loss under simulated microgravity. Atp6v1h+/- mice exhibited bone loss due to Atp6v1h deficiency but did not present aggravated bone loss under the same simulated microgravity. Transcriptomic sequencing revealed the upregulation of genes, such as Fos, Src, Jun, and various integrin subunits in the context of simulated microgravity and Atp6v1h knockout. Real-time quantitative polymerase chain reaction (RT-qPCR) further validated the modulation of downstream osteoclast-related genes in response to interactions with ATP6V1H overexpression cell lines. Co-immunoprecipitation indicated potential interactions between ATP6V1H and integrin beta 1, beta 3, beta 5, alpha 2b, and alpha 5. Our results indicate that Atp6v1h level influences bone loss in simulated microgravity by modulating the Fos-Jun-Src-Integrin pathway, which, in turn, affects osteoclast activity and bone resorption, with implications for osteoporosis. Therefore, modulating Atp6v1h expression could mitigate bone loss in microgravity conditions. This study elucidates the molecular mechanism of Atp6v1h's role in osteoporosis and positions it as a potential therapeutic target against environmental bone loss. These findings open new possibilities for the treatment of multifactorial osteoporosis.
Insights
The gene Atp6v1h influences bone loss in simulated microgravity by affecting osteoclast activity. Modulating Atp6v1h may prevent microgravity-induced bone loss and treat osteoporosis.
Area of Science:
- Biomedical Science
- Molecular Biology
- Space Medicine
Background:
- Microgravity causes significant bone loss, a critical concern for astronauts.
- The gene Atp6v1h is linked to bone loss, but its role in microgravity-induced bone remodeling is unclear.
Purpose of the Study:
- To investigate the role of Atp6v1h in microgravity-induced bone loss.
- To elucidate the molecular mechanisms by which Atp6v1h affects bone remodeling under simulated microgravity.
Main Methods:
- Utilized a mouse tail suspension model to simulate microgravity.
- Employed micro-CT, histology, gene expression analysis (RNA-seq, RT-qPCR), and co-immunoprecipitation.
Main Results:
- Simulated microgravity induced bone loss in wild-type mice.
- Atp6v1h knockout mice showed bone loss but no aggravation under simulated microgravity.
- Identified the Fos-Jun-Src-Integrin pathway as modulated by Atp6v1h in microgravity, affecting osteoclast activity.
Conclusions:
- Atp6v1h level impacts microgravity-induced bone loss by regulating osteoclast function via the Fos-Jun-Src-Integrin pathway.
- Atp6v1h is a potential therapeutic target for mitigating bone loss in microgravity and treating multifactorial osteoporosis.
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