Small Heterodimer Partner Negatively Regulates TLR4 Signaling Pathway of Titanium Particles-Induced Osteolysis in Mice

Abstract

Arthroplasty has been widely performed worldwide. However, peri-prosthetic osteolysis and aseptic loosening induced by macrophages activated by wear particles still remain a predominant cause of long term prosthetic failure. Our study aimed to identify the role of small heterodimer partner (SHP) in secretion of proinflammatory cytokines by macrophages through Toll-like Recepters (TLR)s signaling pathway activated by wear particles both in vivo and in vitro. The effect of SHP on activation of TLR4 pathway and secretion of cytokines was observed in RAW264.7 cells and SHP gene over-expressed mice. Expression of TLR4, TRAF6, NEMO complex and proinflammatory cytokine TNF-α in macrophages stimulated by wear particles was up-regulated, while SHP was down-regulated. On the other hand, inhibition of SHP up-regulated the expression of NEMO complex and proinflammatory cytokine TNF-α in RAW264.7 stimulated by wear particles, while over-expression of SHP gene showed an opposite result. Over-expression of SHP gene could inhibit cranial osteolysis induced by wear particles in mice model. In conclusion, SHP down-regulates TLR4 signaling pathway to reduce osteolysis induced by titanium particles via in vitro and in vivo experimental models.