title: OA10 is a novel p38alpha mitogen-activated protein kinase inhibitor that suppresses osteoclast differentiation and bone resorption.
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.
authors.affiliation: The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Clinical Medical College of Nanjing Medical University, Jiangsu, P.R. China.
authors.forename: T
authors.initials: T
authors.lastname: Jiang
authors.forename: A
authors.initials: A
authors.lastname: Qin
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Shao
authors.forename: B
authors.initials: B
authors.lastname: Tian
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Zhai
authors.forename: H W
authors.initials: HW
authors.lastname: Li
authors.forename: Z A
authors.initials: ZA
authors.lastname: Zhu
authors.forename: K R
authors.initials: KR
authors.lastname: Dai
authors.forename: H Zheng
authors.initials: HZ
authors.lastname: Ming
authors.forename: Y P
authors.initials: YP
authors.lastname: Yu
authors.forename: Q
authors.initials: Q
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D010879:Piperazines / Q000008:administration & dosage*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007211:Indoles; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; C000592624:tert-butyl 4-(3-(1H-indole-2-carboxamido)benzoyl)piperazine-1-carboxylate; D048308:Mitogen-Activated Protein Kinase 14
keywords: O10; OSTEOCLAST DIFFERENTIATION; c-Fos-NFATc1; p38alpha