vivit-peptide and Osteolysis

Wear particles released from prosthetic implants can cause periprosthetic osteolysis, a major cause of implant loosening. The aim of this study was to investigate the effects of the 11R-VIVIT peptide on osteolysis induced by titanium (Ti) particles in vivo. Twenty-four C57BL/J6 mice were divided into 3 groups: sham operation, Ti group, and Ti/VIVIT group. A calvarial osteolysis model was established by implanting Ti particles into mouse calvaria of the Ti and Ti/VIVIT groups. After 2 weeks, 11R-VIVIT peptide (10 mg/kg/day) was intraperitoneally injected into the mice of the Ti/VIVIT group for 14 days. The other 2 groups received saline injection. The calvarial specimens were removed and stained with van Geison staining. The calvarial sagittal suture area was measured to observe bone resorption. The calvarial new bone area was measured to observe bone formation. Compared with the sham group, the area of calvarial new bone and calvarial sagittal suture were higher in the Ti group (P < 0.01). Compared with the Ti group, the area of calvarial new bone was higher and the area of calvarial sagittal suture was lower in the Ti/VIVIT group (P < 0.01). In conclusion, the 11R-VIVIT peptide inhibited bone resorption and enhanced bone formation. This may have contributed to lower wear particle-induced osteolysis. This method could eventually be used to prevent prosthesis loosening after joint replacement and to prolong the life of the prosthesis.

Topics: Animals; Drug Administration Schedule; Injections, Intraperitoneal; Male; Mice, Inbred C57BL; Oligopeptides; Osteoclasts; Osteogenesis; Osteolysis; Prostheses and Implants; Prosthesis Failure; Research Design; Skull; Titanium

Particle-induced periprosthetic osteolysis is the major cause for orthopedic implant failure. This failure is mediated mainly by the action of osteoclasts, the principal cells responsible for bone resorption and osteolysis. Therapeutic interventions to alleviate osteolysis have been focused on understanding and targeting mechanisms of osteoclastogenesis. The nuclear transcription factor NFAT is an essential terminal differentiation factor of osteoclastogenesis. This transcription factor is known to cooperate with c-jun/AP-1 in mediating RANKL-induced osteoclastogenesis. We have previously determined that RANKL is an essential cytokine mediator of particle-induced osteoclastogenesis, and that PMMA particles activate JNK and c-jun/AP-1 in bone marrow macrophages (osteoclast precursors). In the current study, we investigated the effect of PMMA particles on the NFAT signaling pathway in osteoclast precursor cells. Our findings point out that PMMA particles stimulate nuclear translocation of NFAT2 in wild-type osteoclast precursors, which is associated with increased osteoclastogenesis. More importantly, induction of osteoclastogenesis was selectively blocked in a dose-dependent fashion by the calcineurin inhibitors, Cyclosporine-A and FK506. Further, this activation was also blocked in a time-dependent fashion by the NFAT inhibitor VIVIT. Finally, we provide novel evidence that PMMA particles induce binding of NFAT2 and AP-1 proteins. Thus, our findings demonstrate that activation of the NFAT pathway in conjunction with MAP kinases is essential for basal and PMMA-stimulated osteoclastogenesis.

Topics: Animals; Cell Differentiation; Cells, Cultured; Cyclosporine; DNA; Immunosuppressive Agents; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NF-kappa B; NFATC Transcription Factors; Oligopeptides; Osteoclasts; Osteolysis; Polymethyl Methacrylate; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; RANK Ligand; Signal Transduction; Tacrolimus