lignans and Osteolysis

Wear particle-induced bone resorption leads to prosthesis loosening, which is a major complication associated with total joint arthroplasty. Although the exact mechanism remains unclear, wear particle-induced extensive osteoclastogenesis plays a critical role in this process. Thus, a potential treatment of prosthetic loosening is focused on suppressing extensive osteoclast formation and bone resorption, which prevents wear particle-induced osteolysis. Arctigenin isolated from Arctium lappa has numerous beneficial pharmacologic effects, including anti-inflammatory, antiviral, and anticancer activities. Here, we explored the potential impact of arctigenin on titanium (Ti) particle-induced osteolysis in vivo. Our data showed that arctigenin significantly suppressed Ti particle-induced osteolysis and prevented bone destruction compared with Ti group. In addition, the number of osteoclasts reduced after treatment with arctigenin in vivo, indicating osteoclastogenesis might be inhibited by arctigenin. Next, bone marrow-derived macrophages were used to examine osteoclast differentiation, bone resorption, and activation of osteoclast-related signaling pathways. The results showed that arctigenin inhibited RANKL-induced osteoclastogenesis without any cytotoxicity and suppressed osteoclastic marker genes expression and hydroxyapatite resorption activity in a dose-dependent manner. Additionally, arctigenin suppressed receptor activator of nuclear factor κΒ (NF-κB) ligand-induced NF-κB activation, concomitant with retarded IκBɑ degradation and inhibition of p65 nuclear translocation, leading to impaired osteoclastogenesis. Collectively, our results suggest that arctigenin is a promising candidate for the treatment of osteoclast-related osteolytic diseases caused by excessive osteoclast formation.

Topics: Animals; Arthroplasty, Replacement; Bone Resorption; Cell Proliferation; Disease Models, Animal; Durapatite; Furans; Gene Expression Regulation, Developmental; Humans; Lignans; Mice; Osteoclasts; Osteogenesis; Osteolysis; Prostheses and Implants; RANK Ligand; Titanium; Transcription Factor RelA

Receptor activator of NF-κB ligand (RANKL) plays critical role in osteoclastogenesis. Targeting RANKL signaling pathways has been a promising strategy for treating osteoclast related bone diseases such as osteoporosis and aseptic prosthetic loosening. Schisantherin A (SA), a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent, but its effect on osteoclasts has been hitherto unknown. In the present study, SA was found to inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, SA inhibited OSCAR, cathepsin K and TRAP in a dose dependent manner. Further signal transduction studies revealed that SA down-regulate RANKL-induced nuclear factor-kappaB (NF-κB) signaling activation by suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the NF-κB transcriptional activity. Moreover, SA also decreased the RANKL-induced MAPKs signaling pathway, including JNK and ERK1/2 posphorylation while had no obvious effects on p38 activation. Finally, SA suppressed the NF-κB and MAPKs subsequent gene expression of NFATc1 and c-Fos. In vivo studies, SA inhibited osteoclast function and exhibited bone protection effect in wear-particle-induced bone erosion model. Taken together, SA could attenuate osteoclast formation and wear particle-induced osteolysis by mediating RANKL signaling pathways. These data indicated that SA is a promising therapeutic natural compound for the treatment of osteoclast-related prosthesis loosening.

Topics: Animals; Bone Resorption; Cell Differentiation; Cell Survival; Cyclooctanes; Dioxoles; Disease Models, Animal; Lignans; Mice; Mice, Inbred C57BL; NF-kappa B; NFATC Transcription Factors; Osteoclasts; Osteolysis; RANK Ligand; Signal Transduction