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 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.

Uncarboxylated osteocalcin promotes osteogenesis and inhibits adipogenesis of mouse bone marrow‑derived mesenchymal stem cells via the PKA‑AMPK‑SIRT1 axis

“…Studies have shown that osteoporosis is related to the adipogenic differentiation and aging of BMSCs (40,44). At the same time, promoting the osteogenic differentiation of BMSCs has predictable help in treating or reducing osteoporosis (45,46). Although the regulation and shift of the cell differentiation of BMSCs to osteoblasts rather than adipocytes is needed for the treatment of osteoporosis, the molecular mechanism responsible for this regulation of BMSCs has not been defined (39).…”

The Involvement of Long Non-Coding RNAs in Bone

“…Functionally, in the first study [93], the authors proposed that GAS5 significantly increases RUNX2 expression through regulating miR-498, thereby inhibiting the progression of OP. At the same time, Li et al [91] also found that lncRNA GAS5 expression was downregulated in bone tissue and cells derived from osteoporotic patients and that its adenovirus-mediated overexpression promoted osteogenesis both in vitro and in vivo via the regulation of UPF1/SMAD7 axis.…”

“…In addition, some studies have revealed that lncRNA GAS5 could control osteogenic and adipogenic fates of hBMSCs [45,91,92]. However, its role and the effect on osteogenesis, and therefore its potential application as a diagnostic and therapeutic strategy against OP, need to be clarified.…”

IRF2‐mediated upregulation of lncRNA HHAS1 facilitates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cells by acting as a competing endogenous RNA

“…The experiment was performed as previously described. 19 Briefly, 8-week-old C57 mice were anesthetized by chloral hydrate. An incision was made in the cranial skin.…”