Wnt3a-induced LRP6 phosphorylation enhances osteoblast differentiation to alleviate osteoporosis through activation of mTORC1/β-catenin signaling

Objective

Osteoporosis (OP) is a common cause of morbidity and mortality in older individuals. The importance of Wnt3a in osteogenic activity and bone tissue homeostasis is well known. Here, we explored the possible molecular mechanism by which Wnt3a mediates the LRP6/mTORC1/β-catenin axis to regulate osteoblast differentiation in OP.

Methods

OP-related key genes were identified through a bioinformatics analysis. A ROS17/2.8 cell differentiation system for rat osteogenic progenitors and a rat model of senile OP were constructed for in vitro and in vivo mechanism verification.

Results

Bioinformatics analysis revealed that LRP6 was poorly expressed in OP and may play a key role in the occurrence of OP by affecting osteoblast differentiation. LRP6 knockdown inhibited osteoblast differentiation in an in vitro model. In addition, Wnt3a promoted osteoblast differentiation by inducing LRP6 phosphorylation. Moreover, LRP6 promoted mTORC1 expression, which indirectly promoted β-catenin expression, thus promoting osteoblast differentiation. Finally, an in vivo assay revealed that LRP6 inhibition improved OP.

Conclusion

Our study provides evidence that Wnt3a induces phosphorylation of LRP6 to activate the mTORC1/β-catenin axis, thus promoting osteoblast differentiation and ultimately improving OP in aged rats.