title: The ubiquitin-mediated degradation of Jak1 modulates osteoclastogenesis by limiting interferon-beta-induced inhibitory signaling.
abstract: Interferons (IFNs) have been shown to negatively regulate osteoclastogenesis. In a proteomic study to assess protein expression during osteoclastogenesis, we discovered that the expression level of Jak1 was significantly decreased during the early stage of osteoclast differentiation from mouse bone marrow macrophages (BMMs) upon stimulation with receptor activator of nuclear factor kappaB ligand (RANKL). RANKL induced Jak1 ubiquitination, and a proteasome inhibitor MG132 efficiently blocked the RANKL-induced degradation of Jak1. The expression level of Jak1 correlated with the susceptibility of osteoclast precursors to the negative regulatory effects of IFN-beta on osteoclastogenesis, since preosteoclasts (pOCs) in which Jak1 expression is significantly reduced could proceed with osteoclastogenesis in the presence of IFN-beta. Forced down-regulation of Jak1 by small interfering RNA (siRNA) resulted in the efficient osteoclast differentiation of BMMs in the presence of inhibitory IFN-beta, while overexpression of Jak1 in pOCs elicited IFN-beta-dependent inhibition of osteoclastogenesis. Furthermore, we found that the IFN-beta-induced inhibition of osteoclastogenesis required STAT3 downstream of Jak1. These data suggest that the regulation of Jak1 expression during osteoclast differentiation might serve as an intrinsic mechanism that determines osteoclast lineage commitment by modulating the negative regulation by IFN-beta.
authors.affiliation: Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Korea.
authors.forename: Youngkyun
authors.initials: Y
authors.lastname: Lee
authors.forename: Seok-Won
authors.initials: SW
authors.lastname: Hyung
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Jung
authors.forename: Hyung-Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Judith
authors.initials: J
authors.lastname: Staerk
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Chang
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D053245:RANK Ligand; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C505688:TNFSF11 protein, human; D025801:Ubiquitin; D016899:Interferon-beta; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde