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

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 <i>GAS5</i> in human could negatively regulate the lipoblast/adipocyte differentiation. However, it is still unclear whether <i>GAS5</i> affects osteoblast differentiation and whether <i>GAS5</i> is associated with osteoporosis. Our current research found that <i>GAS5</i> was decreased in the bones and BMSCs, a major origin of osteoblast, of osteoporosis patients. Mechanistically, <i>GAS5</i> promotes the osteoblast differentiation by interacting with UPF1 to degrade <i>SMAD7</i> mRNA. Moreover, a decreased bone mass and impaired bone repair ability were observed in <i>Gas5</i> heterozygous mice, manifesting in osteoporosis. The systemic supplement of <i>Gas5</i>-overexpressing adenoviruses significantly ameliorated bone loss in an osteoporosis mouse model. In conclusion, <i>GAS5</i> promotes osteoblast differentiation by targeting the UPF1/SMAD7 axis and protects against osteoporosis.