Genetic and pharmacological activation of Hedgehog signaling inhibits osteoclastogenesis and attenuates titanium particle-induced osteolysis partly through suppressing the JNK/c-Fos-NFATc1 cascade.

摘要: Rationale: Wear particle-induced periprosthetic osteolysis (PPO) is a common long-term complication of total joint arthroplasty, and represents the major cause aseptic loosening subsequent implant failure. Previous studies have identified central role osteoclast-mediated bone resorption in pathogenesis PPO. Thus, therapeutic approaches inhibiting osteoclast formation activity are considered to be great potential prevent treat this osteolytic disease. Hedgehog (Hh) signaling has been shown play an important promoting osteoblast differentiation formation. While Hh also implicated regulating osteoclastogenesis, whether it can directly inhibit remains controversial. Moreover, its effects on PPO never assessed. In study, we explored cell-autonomous osteoclastogenesis preventing wear osteolysis. Methods: was activated macrophages by genetically ablating Sufu these cells using LysM-Cre or treating them with purmorphamine (PM), pharmacological activator Smoothened (Smo). vitro pathway activation RANKL-induced were evaluated TRAP staining, phalloidin qPCR analyses, assays. vivo evaluation efficacy against performed murine calvarial model titanium μCT histological analyses. Mechanistic details RANKL-treated through Western blot Results: We found that deletion PM treatment potently macrophages, strongly inhibited TRAP+ production, F-actin ring formation, osteoclast-specific gene expression, vitro. Furthermore, administration significantly attenuated loss vivo. Our mechanistic study revealed suppressed JNK downregulated protein levels two key osteoclastic transcriptional factors, c-Fos downstream target NFATc1. Conclusions: Both genetic cell-autonomously protect Mechanistically, hinders partly suppressing JNK/c-Fos-NFATc1 cascade. may serve as promising for prevention other diseases.