GAS5 protects against osteoporosis by targeting UPF1/SMAD7 axis in osteoblast differentiation

• DOI: 10.7554/elife.59079
• Publication Date: 2020-10-02T12:00:17Z
• Authors: Ming Li; Zhongyu Xie; Jinteng Li; Jiajie Lin; Guan Zheng; Wenjie Liu; Su'an Tang; Shuizhong Cen; Guiwen Ye; Zhaofeng Li; Wenhui Yu; Peng Wang; Yanfeng Wu; Huiyong Shen
• Keywords: Male; 0301 basic medicine; bone marrow; QH301-705.5; Science; Blotting, Western; Smad7 Protein; Mice; 03 medical and health sciences; GAS5; Animals; Humans; Biology (General); In Situ Hybridization, Fluorescence; stromal cells; Electrophoresis, Agar Gel; 0303 health sciences; Osteoblasts; Q; R; Cell Differentiation; Cell Biology; osteoporosis; Mice, Inbred C57BL; 13. Climate action; osteoblast differentiation; Trans-Activators; Medicine; Osteoporosis; Female; RNA, Long Noncoding; RNA Helicases

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.