Deacylcynaropicrin Inhibits RANKL-Induced Osteoclastogenesis by Inhibiting NF-κB and MAPK and Promoting M2 Polarization of Macrophages

Osteoimmunology encompasses all aspects of the cross-regulation of bone and the immune system, including various cell types, signalling pathways, cytokines and chemokines, under both homeostatic and pathogenic conditions. A number of key areas are of increasing interest and relevance to osteoimmunology researchers. Although rheumatoid arthritis has long been recognized as one of the most common autoimmune diseases to affect bone integrity, researchers have focused increased attention on understanding how molecular triggers and innate signalling pathways (such as Toll-like receptors and purinergic signalling pathways) related to pathogenic and/or commensal microbiota are relevant to bone biology and rheumatic diseases. Additionally, although most discussions relating to osteoimmune regulation of homeostasis and disease have focused on the effects of adaptive immune responses on bone, evidence exists of the regulation of immune cells by bone cells, a concept that is consistent with the established role of the bone marrow in the development and homeostasis of the immune system. The active regulation of immune cells by bone cells is an interesting emerging component of investigations that seek to understand how to control immune-associated diseases of the bone and joints.

Wear particle-induced aseptic prosthetic loosening is one of the most common reasons for total joint arthroplasty (TJA). Extensive bone destruction (osteolysis) by osteoclasts plays an important role in wear particle-induced peri-implant loosening. Thus, strategies for inhibiting osteoclast function may have therapeutic benefit for prosthetic loosening. Here, we mimicked the process of magnesium (Mg) degradation in vivo and obtained Mg leach liquor (MLL) by immersing pure Mg in culture medium. For the first time, we demonstrated that MLL suppresses osteoclast formation, polarization, and osteoclast bone resorption in vitro. An in vivo assay demonstrated that MLL attenuates wear particle-induced osteolysis. Furthermore, we found that MLL significantly inhibits nuclear factor-κB (NF-κB) activation by retarding inhibitor-κB degradation and subsequent NF-κB nuclear translocation. We also found that MLL attenuates the expression of NFATc1 at both the protein and mRNA levels. These results demonstrate that MLL has anti-osteoclast activity in vitro and prevents wear particle-induced osteolysis in vivo. Collectively, our study suggests that metallic magnesium, one of the orthopedic implants with superior properties, has significant potential for the treatment of osteolysis-related diseases caused by excessive osteoclast formation and function. Copyright © 2014 Elsevier Ltd. All rights reserved.

Periprosthetic osteolysis and subsequent aseptic loosening are common in implant failure, a complication with revision surgery being the only established treatment. Wear particle-induced inflammation and extensive osteoclastogenesis play critical roles in periprosthetic osteolysis. A recent approach in limiting osteolysis is therefore focused on inhibiting osteoclastic bone resorption. This study aimed to investigate the potential impact of icariin, the major ingredient of Epimedium, on titanium particle-induced osteolysis in a mouse calvarial model. Eighty-four male C57BL/J6 mice were divided randomly into four groups. Mice in the sham group underwent sham surgery only, whereas animals in the vehicle, low- and high-concentration icariin groups received titanium particles. Mice in the low- and high-concentration icariin groups were gavage-fed with icariin at 0.1 or 0.3 mg/g/day, respectively, until sacrifice. Mice in the sham and vehicle groups received phosphate-buffered saline daily. After 2 weeks, mouse calvariae were collected for micro-computed tomography, histomorphometry and molecular analysis. Icariin significantly reduced particle-induced bone resorption compared with the vehicle group. Icariin also prevented an increase in receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio and subsequently suppressed osteoclast formation in titanium particle-charged calvariae. In addition, immunohistochemical analysis and enzyme-linked immunosorbent assay showed icariin significantly reduced expression and secretion of tumor necrosis factor-α, interleukin-1β and interleukin-6 in the calvariae of titanium-stimulated mice. Collectively, these results suggest that icariin represents a potential treatment for titanium particle-induced osteolysis and could be developed as a new therapeutic candidate for the prevention and treatment of aseptic loosening.