Submitted March 29, 2007
Accepted September 28, 2007
The ubiquitin-mediated degradation of Jak1 modulates osteoclastogenesis by limiting interferon-
-induced inhibitory signaling
Youngkyun Lee, Seok-Won Hyung, Hee Jung Jung, Hyung-Joon Kim, Judith Staerk, Stefan N. Constantinescu, Eun-Ju Chang, Zang Hee Lee, Sang-Won Lee, and Hong-Hee Kim*
Department of Cell and Developmental Biology, BK21 Program, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea, Republic of
Department of Chemistry, Korea University, Seoul, Korea, Republic of
Ludwig Institute for Cancer Research, Brussels, Belgium
* Corresponding author; email: hhbkim{at}snu.ac.kr.
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 
B 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-
on osteoclastogenesis, since pre-osteoclasts (pOCs) in which Jak1 expression is significantly reduced could proceed with osteoclastogenesis in the presence of IFN-. Forced down-regulation of Jak1 by small interfering RNA resulted in the efficient osteoclast differentiation of BMMs in the presence of inhibitory IFN-, while overexpression of Jak1 in pOCs elicited IFN--dependent inhibition of osteoclastogenesis. Furthermore, we found that the IFN--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-.
