title: The 1,2,3-triazole derivative KP-A021 suppresses osteoclast differentiation and function by inhibiting RANKL-mediated MEK-ERK signaling pathway.
abstract: The triazole family of compounds has been implicated in modulating various biological processes such as inflammation, tumorigenesis, and infection. To our knowledge, this is the first study to demonstrate the effects of 1,2,3-triazole substituted biarylacrylonitrile compounds, including KP-A021, on the differentiation and function of osteoclasts. KP-A021 and its triazole derivatives, at a concentration that does not cause a cytotoxic response in bone marrow macrophages (BMMs), significantly inhibited osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) as assessed by tartrate-resistant acid phosphatase (TRAP) staining. KP-A021 also dramatically inhibited the expression of marker genes associated with osteoclast differentiation, such as TRAP, cathepsin K (Cat K), dendritic cell-specific transmembrane protein (DC-STAMP), and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). Furthermore, KP-A021 inhibited actin ring formation in osteoclasts as well as resorption pit formation induced by osteoclasts. Analysis of the signaling pathway for KP-A021 indicated that this triazole compound inhibited the RANKL-induced activation of extracellular signal-regulated kinase (ERK) and its upstream signaling molecule, mitogen-activated protein kinase kinase1/2 (MEK1/2). Taken together, these results demonstrate that KP-A021 has an inhibitory effect on the differentiation and function of osteoclasts via modulation of the RANKL-induced activation of the MEK-ERK pathway.
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Ihn
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Doohyun
authors.initials: D
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Taeho
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 700-412, Republic of Korea.
authors.forename: Hong-In
authors.initials: HI
authors.lastname: Shin
authors.affiliation: Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Republic of Korea.
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Bae
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 700-412, Republic of Korea epark@knu.ac.kr shkim72@knu.ac.kr.
authors.forename: Eui Kyun
authors.initials: EK
authors.lastname: Park
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D015151:Immunoblotting; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008813:Mice, Inbred ICR; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C000606725:3-(4-fluorophenyl)-2-(4-(1-(3-morpholino-3-oxopropyl)-1H-1,2,3-triazol-4yl)phenyl)acrylonitrile; D050071:Bone Density Conservation Agents; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014230:Triazoles; D000181:Acrylonitrile
keywords: KP-A021; Triazole family; bone resorption; differentiation; osteoclast