The ubiquitin-mediated degradation of Jak1 modulates osteoclastogenesis by limiting interferon-β-induced inhibitory signaling

Youngkyun Lee, Seok Won Hyung, Jung Jung Hee, Hyung Joon Kim, Judith Staerk, Stefan N. Constantinescu, Eun Ju Chang, Hee Lee Zang, Sang-Won Lee, Hong Hee Kim

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29 Citations (Scopus)

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 κB 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-β on osteoclastogenesis, since preosteoclasts (pOCs) in which Jak1 expression is significantly reduced could proceed with osteoclastogenesis in the presence of IFN-β. Forced down-regulation of Jak1 by small interfering RNA (siRNA) resulted in the efficient osteoclast differentiation of BMMs in the presence of inhibitory IFN-β, while overexpression of Jak1 in pOCs elicited IFN-β-dependent inhibition of osteoclastogenesis. Furthermore, we found that the IFN-β-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-β.

Original languageEnglish
Pages (from-to)885-893
Number of pages9
JournalBlood
Volume111
Issue number2
DOIs
Publication statusPublished - 2008 Jan 15

ASJC Scopus subject areas

  • Hematology

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    Lee, Y., Hyung, S. W., Hee, J. J., Kim, H. J., Staerk, J., Constantinescu, S. N., Chang, E. J., Zang, H. L., Lee, S-W., & Kim, H. H. (2008). The ubiquitin-mediated degradation of Jak1 modulates osteoclastogenesis by limiting interferon-β-induced inhibitory signaling. Blood, 111(2), 885-893. https://doi.org/10.1182/blood-2007-03-082941