MiR-92a/KLF4/p110δ regulates titanium particles-induced macrophages inflammation and osteolysis

As total joint replacement is widely applied for severe arthropathy, peri-prosthetic aseptic loosening as one of the main causes of implant failure has drawn wide attention. Wear particles such as titanium particles (TiPs) derived from prosthesis can initiate macrophages inflammation and sequentially activate osteoclasts, which results in bone resorption and osteolysis for long-term. Therefore, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL. In this research, we found that the inhibition of p110 delta, a member of class IA PI3Ks family, could significantly dampen the TiPs-induced secretion of TNF alpha and IL-6. By the transfection of siRNA targeting p110 delta, we confirmed that p110 delta was responsible for TNF alpha and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. As the upstream transcription-repressor of p110 delta, Kruppel-like factor 4 (KLF4), targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-kappa B pathway and M1/M2 polarization. To further ascertain the roles of KLF4/p110 delta, TiPs-induced mice cranial osteolysis model was established and vivo experiments validated that KLF4-knockdown could exacerbate TiPs-induced osteolysis, which was strikingly ameliorated by knockdown of p110 delta. In summary, our study suggests the key role of miR-92a/KLF4/p110 delta signal in TiPs-induced macrophages inflammation and osteolysis.

Automated summary

This study found that inhibiting p110 delta could reduce the inflammation caused by titanium particles, thereby alleviating osteolysis. Additionally, miR-92a and KLF4 also played important roles in suppressing the inflammatory response induced by titanium particles.