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J Cell Biochem ; 115(5): 959-66, 2014 May.
Article in English | MEDLINE | ID: mdl-24357524

ABSTRACT

In search of anti-bone resorbing agents for the potential treatment of osteoporosis, we synthesized a novel compound Tert-butyl 4-(3-[1H-indole-2-carboxamido]benzoyl)piperazine-1-carboxylate (OA10) and found that OA10 is capable of inhibiting RANKL-mediated osteoclast formation and osteoclastic bone resorption in a dose-dependent manner. This biological effect is further supported by the fact that OA10 suppressed osteoclastic-specific gene expression, including tartrate-resistant acid phosphatase, cathepsin K receptor, and calcitonin receptor. Further molecular mechanism investigation revealed OA10 inhibited p38 phosphorylation, suppressed c-fos and NFATc1 expression without affecting NF-κB or JNK signaling pathways. Taken together, this study suggested that OA10 can inhibit osteoclastogenesis by suppressing p38-c-Fos-NFATc1 cascade. OA10 may be developed as a therapeutic drug for osteoclast-related osteolytic diseases.


Subject(s)
Indoles/administration & dosage , Mitogen-Activated Protein Kinase 14/metabolism , Osteoclasts/metabolism , Osteogenesis/drug effects , Piperazines/administration & dosage , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Bone Resorption/drug therapy , Bone Resorption/metabolism , Cell Differentiation/drug effects , Gene Expression Regulation, Developmental/drug effects , Macrophages/drug effects , Macrophages/metabolism , Mice , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , NF-kappa B/metabolism , NFATC Transcription Factors/metabolism , Osteoclasts/cytology , Proto-Oncogene Proteins c-fos/metabolism , RANK Ligand/genetics , RANK Ligand/metabolism , Signal Transduction/drug effects
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