Journal
BIOMATERIALS
Volume 35, Issue 32, Pages 8937-8950Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2014.06.055
Keywords
Total joint arthroplasty; OA-14; Osteoclast; Osteolysis; MAP kinase; NFATc1
Funding
- Key Disciplines of Shanghai Municipal Education Commission
- Natural Science Foundation of China [81301590]
- Science and Technology Commission of Shanghai Municipality [12JC1405600]
- National Natural Science Foundation for the Youth of China [81201364]
- scientific research grant for youth of Shanghai [ZZjdyx 2097]
- scientific research grant from 985 Project-Stem Cell and Regenerative Medicine Centre
- Shanghai Municipal Education Commission
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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 kappa B). Collectively, our results suggest that the compound OA-14 can be safely used for treating particle-induced pen-implant osteolysis and other diseases caused by excessive osteoclast formation and function. (C) 2014 Elsevier Ltd. All rights reserved.
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