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Elife. 2019 Sep 6;8. pii: e42951. doi: 10.7554/eLife.42951.

Regulator of G protein signaling 12 enhances osteoclastogenesis by suppressing Nrf2-dependent antioxidant proteins to promote the generation of reactive oxygen species.

Ng AYH#1,2,3, Li Z#1, Jones MM2, Yang S1, Li C2, Fu C4, Tu C3,5, Oursler MJ6, Qu J3,5, Yang S1,7.

Author information

1
Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, United States.
2
Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, United States.
3
New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, United States.
4
Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
5
Department of Pharmaceutical Science, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, United States.
6
Division of Endocrinology, Metabolism, Nutrition & Diabetes, Mayo Clinic, Rochester, United States.
7
The Penn Center for Musculoskeletal Disorders, School of Medicine, University of Pennsylvania, Philadelphia, United States.
#
Contributed equally

Abstract

Regulators of G-protein Signaling are a conserved family of proteins required in various biological processes including cell differentiation. We previously demonstrated that Rgs12 is essential for osteoclast differentiation and its deletion in vivo protected mice against pathological bone loss. To characterize its mechanism in osteoclastogenesis, we selectively deleted Rgs12 in C57BL/6J mice targeting osteoclast precursors using LyzM-driven Cre mice or overexpressed Rgs12 in RAW264.7 cells. Rgs12 deletion in vivo led to an osteopetrotic phenotype evidenced by increased trabecular bone, decreased osteoclast number and activity but no change in osteoblast number and bone formation. Rgs12 overexpression increased osteoclast number and size, and bone resorption activity. Proteomics analysis of Rgs12-depleted osteoclasts 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 reactive oxygen species 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 NFκB, which was abrogated by antioxidant treatment. Our study therefore identified a novel role of Rgs12 in regulating Nrf2, thereby controlling cellular redox state and osteoclast differentiation.

KEYWORDS:

cell biology; mouse; osteoclasts; proteomics; reactive oxygen species

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