The Effect Of MicroRNA-106b On Wear Debris-induced Periprosthetic Osteolysis And Its Mechanism

Objective:Aseptic loosening caused by periprosthetic osteolysis(PPO)is the primary reason for the primary artificial joint replacement.Inhibition of inflammatory osteolysis has become the main target of drug therapy for prosthesis loosening.MiR-106b is a newly discovered miRNA that plays an important role in tumor biology,inflammation,and the regulation of bone mass.In this study,we analyzed the in vivo effect of miR-106b on wear debris-induced PPO.Methods:A rat implant loosening model was established.The rats were then administrated a lentivirus-mediated miR-106b inhibitor,miR-106b mimics,or an equivalent volume of PBS by tail vein injection.The expression levels of miR-106b were analyzed by real-time PCR.Morphological changes in the distal femurs were assessed via micro-CT and histopathological analysis,and cytokine expression levels were examined via immunohistochemical staining and ELISA.Results:The results showed that treatment with the miR-106b inhibitor markedly suppressed the expression of miR-106b in distal femur and alleviated titanium particle-induced osteolysis and bone loss.Statistical analysis showed that after treatment with miR-106b inhibitor,osteolysis was decreased and the BMD(0.7301 ± 0.0088 g/cc vs.0.7078 ± 0.0061 g/cc),BS/BV(38.57 ± 4.41%vs.49.43 ± 3.61%),BV/TV(19.46±1.975%vs.15.95 ± 0.33%),and Tb.Th(0.09161 ± 0.00510 mm vs.0.07672±0.00246 mm)were dramatically reversed from those in the vehicle group(P<0.05).The measurement results also showed that the miR-106b inhibitor-treated group had the lowest Tb.Sp(0.01531±0.00291 ?m)and the highest Tb.N(15.35±2.28 mm-1),and the difference was statistically significant compared with the vehicle group(P<0.05).Moreover,the miR-106b inhibitor decreased TRAP-positive cell numbers and suppressed osteoclast formation,in addition to promoting the activity of osteoblasts and increasing bone formation.Bone tissue metrology analysis showed that Oc.S/BS and N.Oc/BS remarkably increased after the addition of Ti particles and significantly decreased after treatment with the miR-106b inhibitor(26.67±3.37%vs.6.18±2.47%;39.06±5.15 mm-2 vs.16.84±4.07 mm-2,P<0.05).In addition,immunohistochemical staining results showed that CTSK and MMP-9 expression around the Ti implants were also significantly inhibited after treatment with the miR-106b inhibitor.The serum levels of CTX-1 and TRAP5b decreased significantly after treatment with the miR-106b inhibitor.MiR-106b inhibition also significantly regulated macrophage polarization and decreased the inflammatory response as compared to the control group.Furthermore,miR-106b inhibition blocked the activation of the PTEN/PI3K/AKT and NF-?B signaling pathways.Conclusions:Our findings indicated that miR-106b inhibition suppresses wear particles-induced osteolysis and bone destruction and thus may serve as a potential therapeutic for PPO and aseptic loosening.