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

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 an lncRNA named GAS5 in humans
could negatively regulate 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, in osteoporosis patients. Mechanistically, GAS5 promotes
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.