title: Pyridone 6, a pan-Janus-activated kinase inhibitor, suppresses osteoclast formation and bone resorption through down-regulation of receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced c-Fos and nuclear factor of activated T cells (NFAT) c1 expression.
abstract: It has been reported that Janus tyrosine kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of numerous malignancies and immune reactions, and inhibition of JAK has been implicated in cell growth inhibition. The role which JAK has on osteoclast differentiation and anti-bone resorptive activity is not well understood. In this study, we investigated the effects of a pan-JAK inhibitor, pyridone 6, on osteoclast differentiation and bone-resorption in vitro and ex vivo. Pyridone 6 inhibited osteoclast differentiation in mouse bone marrow macrophage (BMM) cultures stimulated by the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) and co-cultures of bone marrow cells and osteoblasts. Pyridone 6 suppressed the expression of c-Fos and nuclear factor of activated T cells (NFAT) c1 in BMMs. It also inhibited the bone resorptive activity of mature osteoclasts that was accompanied by disruption of actin rings. Pyridone 6 also suppressed I-kappaB degradation and extracellular signal-regulated kinase (ERK) in mature osteoclasts, suggesting that these are the key molecules that pyridone 6 targets in the inhibition of osteoclast function. These results demonstrate inhibition of JAK may be useful for the treatment of bone-resorptive diseases, such as osteoporosis.
authors.affiliation: Department of Anatomy, Wonkwang University, Jeonbuk, Korea.
authors.forename: Han Bok
authors.initials: HB
authors.lastname: Kwak
authors.forename: Hun Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Myeung Su
authors.initials: MS
authors.lastname: Lee
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Kim
authors.forename: Eun-Yong
authors.initials: EY
authors.lastname: Choi
authors.forename: Min-Kyu
authors.initials: MK
authors.lastname: Choi
authors.forename: Jeong-Joong
authors.initials: JJ
authors.lastname: Kim
authors.forename: Hae Joong
authors.initials: HJ
authors.lastname: Cho
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Ji-Myung
authors.initials: JM
authors.lastname: Bae
authors.forename: Yun-Kyung
authors.initials: YK
authors.lastname: Kim
authors.forename: Byoung Hyun
authors.initials: BH
authors.lastname: Park
authors.forename: Hyunil
authors.initials: H
authors.lastname: Ha
authors.forename: Churl Hong
authors.initials: CH
authors.lastname: Chun
authors.forename: Jaemin
authors.initials: J
authors.lastname: Oh
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C524063:2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D011728:Pyridones; D053245:RANK Ligand