Rgs12 enhances osteoclastogenesis by suppressing Nrf2 activity and promoting the formation of reactive oxygen species

• Published in: bioRxiv
• Main Authors: Hui Ng, Andrew Ying, Li, Ziqing, Jones, Megan M, Tu, Chengjian, Oursler, Merry Jo, Qu, Jun, Yang, Shuying
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.11.2018
• Subjects: Antioxidants; Bone loss; Bone mass; Clonal deletion; Gene deletion; Gene regulation; Osteoclastogenesis; Oxidative stress; Phosphorylation; Proteasome 26S; Proteomics; Reactive oxygen species; Redox properties; TRANCE protein; Transcription
• DOI: 10.1101/470542

The Regulator of G-protein Signaling 12 (Rgs12) is important for osteoclast (OC) differentiation, and its deletion in vivo protected mice against pathological bone loss. To characterize its mechanism in osteoclastogenesis, we selectively deleted Rgs12 in OC precursors using the LysM-Cre transgenic line or overexpressed the gene in RAW264.7 cells. Rgs12 deletion led to increased bone mass with decreased OC numbers, whereas its overexpression increased OC number and size. Proteomics analysis of Rgs12-deficient OCs identified an upregulation of antioxidant enzymes under the transcriptional regulation of Nrf2, the master regulator of oxidative stress. We confirmed an increase of Nrf2 activity and impaired production in Rgs12-deficient cells. Conversely, Rgs12 overexpression suppressed Nrf2 through a mechanism dependent on the 26S proteasome, and promoted RANKL-induced phosphorylation of ERK1/2 and NF B, which was abrogated by antioxidant treatment. We therefore identified a novel role of Rgs12 in regulating Nrf2, thereby controlling cellular redox state and OC differentiation.