RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146.
Bone undergoes continuous remodeling due to balanced bone formation and resorption mediated by osteoblasts and osteoclasts, respectively. Osteoclasts arise from the macrophage lineage, and their differentiation is dependent on RANKL, a member of the TNF family of cytokines. Here, we have provided ev...
| Published in: | Journal of Clinical Investigation Vol. 127; no. 4; pp. 1303 - 1316 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | Journal Article |
| Published: |
American Society for Clinical Investigation
4/3/2017
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=122353790&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 122353790 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00219738 0YX jtl: Journal of Clinical Investigation issn: 00219738 maglogo: N pubinfo: dt: 4/3/2017 vid: 127 iid: 4 pid: 11983 pub: American Society for Clinical Investigation place: Ann Arbor, Michigan artinfo: ui: 122353790 122353790 NLM28287403 10.1172/JCI90527 NLM28287403 122353790 ppf: 1303 ppct: 13 formats: tig: atl: RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146. aug: au: Yoshinori Matsumoto Larose, Jose Kent, Oliver A. Lim, Melissa Changoor, Adele Zhang, Lucia Storozhuk, Yaryna Xiaohong Mao Grynpas, Marc D. Feng Cong Rottapel, Robert Matsumoto, Yoshinori Mao, Xiaohong Cong, Feng affil: Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada sug: ab: Bone undergoes continuous remodeling due to balanced bone formation and resorption mediated by osteoblasts and osteoclasts, respectively. Osteoclasts arise from the macrophage lineage, and their differentiation is dependent on RANKL, a member of the TNF family of cytokines. Here, we have provided evidence that RANKL controls the expression of 3BP2, an adapter protein that is required for activation of SRC tyrosine kinase and simultaneously coordinates the attenuation of β-catenin, both of which are required to execute the osteoclast developmental program. We found that RANKL represses the transcription of the E3 ubiquitin ligase RNF146 through an NF-κB-related inhibitory element in the RNF146 promoter. RANKL-mediated suppression of RNF146 results in the stabilization of its substrates, 3BP2 and AXIN1, which consequently triggers the activation of SRC and attenuates the expression of β-catenin, respectively. Depletion of RNF146 caused hypersensitivity to LPS-induced TNF-α production in vivo. RNF146 thus acts as an inhibitory switch to control osteoclastogenesis and cytokine production and may be a control point underlying the pathogenesis of chronic inflammatory diseases. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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