OA10 Is a Novel p38alpha Mitogen-Activated Protein Kinase Inhibitor That Suppresses Osteoclast Differentiation and Bone Resorption

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-B 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. J. Cell. Biochem. 115: 959-966, 2014. (c) 2013 Wiley Periodicals, Inc.