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.
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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.
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GAS5 protects against osteoporosis by targeting UPF1/SMAD7 axis in osteoblast differentiation
eLife 9:e59079.
https://doi.org/10.7554/eLife.59079
Further reading
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- Cell Biology
- Developmental Biology
Eukaryotic cells depend on exocytosis to direct intracellularly synthesized material toward the extracellular space or the plasma membrane, so exocytosis constitutes a basic function for cellular homeostasis and communication between cells. The secretory pathway includes biogenesis of secretory granules (SGs), their maturation and fusion with the plasma membrane (exocytosis), resulting in release of SG content to the extracellular space. The larval salivary gland of Drosophila melanogaster is an excellent model for studying exocytosis. This gland synthesizes mucins that are packaged in SGs that sprout from the trans-Golgi network and then undergo a maturation process that involves homotypic fusion, condensation, and acidification. Finally, mature SGs are directed to the apical domain of the plasma membrane with which they fuse, releasing their content into the gland lumen. The exocyst is a hetero-octameric complex that participates in tethering of vesicles to the plasma membrane during constitutive exocytosis. By precise temperature-dependent gradual activation of the Gal4-UAS expression system, we have induced different levels of silencing of exocyst complex subunits, and identified three temporarily distinctive steps of the regulated exocytic pathway where the exocyst is critically required: SG biogenesis, SG maturation, and SG exocytosis. Our results shed light on previously unidentified functions of the exocyst along the exocytic pathway. We propose that the exocyst acts as a general tethering factor in various steps of this cellular process.
