GAS5 protects against osteoporosis by targeting UPF1/SMAD7 axis in osteoblast differentiation
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
- The Eighth Affiliated Hospital, Sun Yat-sen University, China
- Zhujiang Hospital, Southern Medical University, China
Abstract
Osteoporosis is a common systemic skeletal disorder resulting in bone fragility and increased fracture risk. It is still necessary to explore its detailed mechanisms and identify novel targets for the treatment of osteoporosis. Previously, we found that a lncRNA named GAS5 in human could negatively regulate the lipoblast/adipocyte differentiation. However, it is still unclear whether GAS5 affects osteoblast differentiation and whether GAS5 is associated with osteoporosis. Our current research found that GAS5 was decreased in the bones and BMSCs, a major origin of osteoblast, of osteoporosis patients. Mechanistically, GAS5 promotes the osteoblast differentiation by interacting with UPF1 to degrade SMAD7 mRNA. Moreover, a decreased bone mass and impaired bone repair ability were observed in Gas5 heterozygous mice, manifesting in osteoporosis. The systemic supplement of Gas5-overexpressing adenoviruses significantly ameliorated bone loss in an osteoporosis mouse model. In conclusion, GAS5 promotes osteoblast differentiation by targeting the UPF1/SMAD7 axis and protects against osteoporosis.
Data availability
The relevant data are available from Dryad (DOI: https://doi.org/10.5061/dryad.9cnp5hqfj). Primers of the analyzed genes (Supplementary Table 1), the siRNA sequences of the analyzed genes (Supplementary Table 2), characteristics of the study subjects (Supplementary Table 3) and Characteristics of the 15 healthy donors (Supplementary Table 4) can be found in the supplementary documents.
-
GAS5 protects against osteoporosis by targeting UPF1/Smad7 axis in osteoblast differentiationDryad Digital Repository, doi:10.5061/dryad.9cnp5hqfj.
Article and author information
Author details
Funding
National Natural Science Foundation of China (81971518,81672097,81871750,81702120)
- Zhongyu Xie
- Peng Wang
- Yanfeng Wu
- Huiyong Shen
Ken Realm R&D Program of Guangdong Province (2019B020236001)
- Huiyong Shen
Fundamental Research Funds for the Central Universities (19ykpy01)
- Zhongyu Xie
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of Eighth Affiliated Hospital of Sun Yat-sen University. All procedures involving animals were approved by the Animal Use and Care Committee of the Eighth Affiliated Hospital of Sun Yat-sen University (approval number: SYSU-IACUC-2018-B10325).
Human subjects: The study was approved by the ethics committee of the Eighth Affiliated Hospital of Sun Yat-sen University (approval number: 2018r010) and it was performed in strict accordance with the recommendations of ethics committee. After explaining in detail the possible risks and importance of the research, as well as informing methods of privacy protection, we obtained the informed consent and consent publish signatures of all patients or normal donors.
Copyright
© 2020, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,284
- views
-
- 240
- downloads
-
- 30
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
GAS5 protects against osteoporosis by targeting UPF1/SMAD7 axis in osteoblast differentiation
eLife 9:e59079.
https://doi.org/10.7554/eLife.59079
Further reading
-
- Cell Biology
- Neuroscience
It has been well validated that chronic psychological stress leads to bone loss, but the underlying mechanism remains unclarified. In this study, we established and analyzed the chronic unpredictable mild stress (CUMS) mice to investigate the miRNA-related pathogenic mechanism involved in psychological stress-induced osteoporosis. Our result found that these CUMS mice exhibited osteoporosis phenotype that is mainly attributed to the abnormal activities of osteoclasts. Subsequently, miRNA sequencing and other analysis showed that miR-335-3p, which is normally highly expressed in the brain, was significantly downregulated in the nucleus ambiguous, serum, and bone of the CUMS mice. Additionally, in vitro studies detected that miR-335-3p is important for osteoclast differentiation, with its direct targeting site in Fos. Further studies demonstrated FOS was upregulated in CUMS osteoclast, and the inhibition of FOS suppressed the accelerated osteoclastic differentiation, as well as the expression of osteoclastic genes, such as Nfatc1, Acp5, and Mmp9, in miR-335-3p-restrained osteoclasts. In conclusion, this work indicated that psychological stress may downregulate the miR-335-3p expression, which resulted in the accumulation of FOS and the upregulation of NFACT1 signaling pathway in osteoclasts, leading to its accelerated differentiation and abnormal activity. These results decipher a previously unrecognized paradigm that miRNA can act as a link between psychological stress and bone metabolism.
