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

Ming Li,Yanfeng Wu,Zhaofeng Li,Zhongyu Xie,Huiyong Shen,Shuizhong Cen,Su'An Tang,Jiajie Lin,Guan Zheng,Guiwen Ye,Wenhui Yu,Jinteng Li,Wenjie Liu,Peng Wang

doi:10.7554/elife.59079

Ming Li, Yanfeng Wu + Show 12 more

Open Access

https://doi.org/10.7554/elife.59079

Copy DOI

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.

Highlights

Osteoporosis is a systemic skeletal disease that manifests as low bone mass and microarchitectural deterioration of bone tissue (Yang et al, 2020)
The mRNA level of GAS5 in both bone tissues and bone marrow stromal cells (BMSCs) was decreased in patients with osteoporosis compared to in those with hip dysplasia and normal control (Figure 1B–C), which indicated that GAS5 expression was closely related to bone metabolism in osteoporosis
Given the crucial role of BMSCs in osteoporosis, we explored the variation tendency of GAS5 expression during osteoblast differentiation of BMSCs

Summary

Introduction

Osteoporosis is a systemic skeletal disease that manifests as low bone mass and microarchitectural deterioration of bone tissue (Yang et al, 2020). Individuals with osteoporosis are at a higher risk of fragility fractures (Eastell et al, 2016). Over 200 million people worldwide suffer from this disease, and this number is gradually increasing (Lizneva et al, 2018). Fractures caused by osteoporosis lead to functional disruption and pain along with an enormous therapeutic cost. In the United States and European Union, osteoporotic fractures have been estimated to cost $20 billion to $30 billion annually (Lorentzon, 2019). Many studies on osteoporosis have been conducted in recent years, more effective diagnostic and curative targets need to be explored for osteoporosis

Methods

Results

Conclusion