The prevention of titanium-particle-induced osteolysis by OA-14 through the suppression of the p38 signaling pathway and inhibition of osteoclastogenesis.
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.
['Tian|Bo|B|', 'Jiang|Tao|T|', 'Shao|Zhanying|Z|', 'Zhai|Zanjing|Z|', 'Li|Haowei|H|', 'Fan|Qiming|Q|', 'Liu|Xuqiang|X|', 'Ouyang|Zhengxiao|Z|', 'Tang|Tingting|T|', 'Jiang|Qing|Q|', 'Zheng|Minghao|M|', 'Dai|Kerong|K|', 'Qin|An|A|', 'Yu|Yongping|Y|', 'Zhu|Zhenan|Z|']
D000135:Acid Phosphatase D000199:Actins D000818:Animals D001549:Benzamides D001862:Bone Resorption D002470:Cell Survival D002478:Cells, Cultured D007211:Indoles D007527:Isoenzymes D020935:MAP Kinase Signaling System D051379:Mice D008810:Mice, Inbred C57BL D010010:Osteoclasts D010014:Osteolysis D053245:RANK Ligand D000071681:Tartrate-Resistant Acid Phosphatase D014025:Titanium
Osteolysis OA-14 Osteoclast MAP kinase NFATc1 Total joint arthroplasty