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Biochem Biophys Res Commun ; 514(4): 1244-1250, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31109651

RESUMO

Wear particle-induced osteolysis around the prosthesis is the most common long-term complication after total joint replacement surgery which often leads to aseptic loosening of the prosthesis. Osteoclasts play key roles in the osteolytic process. Currently there is a lack of clinically effective measures to prevent or treat peri-prosthetic osteolysis and thus identification of new agents that can inhibit the enhanced osteoclastic bone resorption is warranted. Through this study, we discovered that the specific and potent ERK1/2 inhibitor, Vx-11e, can protect against calvarial osteolysis caused by titanium (Ti) particles in vivo. Low doses of Vx-11e mildly reduced osteoclast resorption whilst no calvarial osteolysis was observed with high dose Vx-11e treatment. Histological examination showed fewer osteoclasts and reduced bone erosion in the Vx-11e treated groups. In vitro cellular analyses showed that Vx-11e inhibited osteoclast formation from BMM precursors in response to RANKL, as well as bone resorption by mature osteoclasts. Mechanistically, Vx-11e impaired RANKL-induced ERK1/2 signaling by inhibiting its kinase activity thereby blocking the phosphorylation of downstream substrates. Moreover, Vx-11e significantly reduced the expression of RANKL-mediated genes such as ACP5/TRAcP, CTR, MMP-9, CTSK. Collectively, our data provides evidence for the potential therapeutic use of Vx-11e for the treatment of osteolysis diseases caused by extremely actived osteoclastogenesis.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Substâncias Protetoras/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirróis/química , Titânio/química , Titânio/farmacologia
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