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J Cell Physiol. 2019 Feb;234(2):1659-1670. doi: 10.1002/jcp.27035. Epub 2018 Aug 4.

Estrogen-related receptor γ negatively regulates osteoclastogenesis and protects against inflammatory bone loss.

Author information

1
Department of Molecular Medicine, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
2
Clinical Trial Center, Kyungpook National University Hospital, Daegu, Republic of Korea.

Abstract

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor that plays an important role in various metabolic processes under physiological and pathophysiological conditions. Here, we report that ERRγ functions as a negative regulator in receptor activator of nuclear factor κΒ ligand (RANKL)-induced osteoclast differentiation. We observed that ERRγ was strongly expressed in osteoclast precursors, bone marrow-derived macrophages (BMMs) while its expression was significantly reduced by RANKL during osteoclastogenesis. Overexpression of ERRγ in BMMs suppressed the formation of multinucleated osteoclasts and attenuated the induction of c-Fos and nuclear factor of activated T cells c1, which are critical modulators in osteoclastogenesis. Similarly, the treatment of ERRγ agonists, N-(4-(diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) or GSK4716, also inhibited osteoclast generation and the expression of these key modulators. On the other hand, shRNA-mediated knockdown of ERRγ accelerated the formation of bone-resorbing cells and the expression of osteoclastogenic markers. Forced expression of ERRγ blocked RANKL-stimulated phosphorylation of the nuclear factor κB (NF-κB) inhibitor IκBα and suppressed NF-κB transcriptional activity induced by RANKL or the NF-κB subunit p65. Furthermore, by employing a pharmacological approach, we showed that the ERRγ agonist DY131 protected against inflammatory bone loss induced by lipopolysaccharide in vivo. Together, our findings reveal that ERRγ is a pivotal regulator in RANKL-mediated osteoclastogenesis and suggest that ERRγ may have potential as a therapeutic target for pathological bone loss.

KEYWORDS:

ERRγ; NF-κB; NFATc1; osteoclastogenesis

PMID:
30076703
DOI:
10.1002/jcp.27035

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