The prevention of titanium-particle-induced osteolysis by OA-14 through the suppression of the p38 signaling pathway and inhibition of osteoclastogenesis.

Abstract

Wear-particle-induced osteolysis leads to prosthesis loosening, which is one of the most common causes of joint-implant failure, a problem that must be fixed using revision surgery. Thus, a potential treatment for prosthetic loosening is focused on inhibiting osteoclastic bone resorption, which prevents wear-particle-induced osteolysis. In this study, we synthesized a compound named OA-14 (N-(3- (dodecylcarbamoyl)phenyl)-1H-indole-2-carboxamide) and examined how OA-14 affects titanium (Ti)-particle-induced osteolysis and osteoclastogenesis. We report that OA-14 treatment protected against Ti-particle-induced osteolysis in a mouse calvarial model. Interestingly, the number of tartrate-resistant acid phosphatase-positive osteoclasts decreased after treatment with OA-14 in vivo, which suggested that OA-14 inhibits osteoclast formation. To test this hypothesis, we conducted in vitro studies, and our results revealed that OA-14 markedly diminished osteoclast differentiation and osteoclast-specific gene expression in a dose- and time-dependent manner. Moreover, OA-14 suppressed osteoclastic bone resorption and F-actin ring formation. Furthermore, we determined that OA-14 inhibited osteoclastogenesis by specifically blocking the p38-Mitf-c-fos-NFATc1 signaling cascade induced by RANKL (ligand of receptor activator of nuclear factor κB). Collectively, our results suggest that the compound OA-14 can be safely used for treating particle-induced peri-implant osteolysis and other diseases caused by excessive osteoclast formation and function.

• Authors: Bo Tian, Tao Jiang, Zhanying Shao, Zanjing Zhai, Haowei Li, Qiming Fan, Xuqiang Liu, Zhengxiao Ouyang, Tingting Tang, Qing Jiang, Minghao Zheng, Kerong Dai, An Qin, Yongping Yu, Zhenan Zhu
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 32 Pg. 8937-50 (Oct 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 25086794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Actins
• Benzamides
• Indoles
• Isoenzymes
• N-(3-(dodecylcarbamoyl)phenyl)-1H-indole-2-carboxamide
• RANK Ligand
• Tnfsf11 protein, mouse
• Titanium
• Acid Phosphatase
• Tartrate-Resistant Acid Phosphatase

Topics

• Acid Phosphatase (metabolism)
• Actins (metabolism)
• Animals
• Benzamides (pharmacology)
• Bone Resorption (drug therapy)
• Cell Survival (drug effects)
• Cells, Cultured
• Indoles (pharmacology)
• Isoenzymes (metabolism)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mice, Inbred C57BL
• Osteoclasts (drug effects, metabolism)
• Osteolysis (chemically induced, drug therapy)
• RANK Ligand (metabolism)
• Tartrate-Resistant Acid Phosphatase
• Titanium (adverse effects)