PARG inhibition suppresses osteoclast differentiation through transcriptional activation of an NRF2-dependent pathway
- 1Department of Pharmacology, School of Dentistry, Osaka Dental University, Hirakata, Osaka, Japan
- 2Department of Molecular and Genomic Biomedicine, Center for Bioinformatics and Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan
Abstract
Poly (ADP-ribose) glycohydrolase (PARG) is the main enzyme responsible for degrading poly (ADP-ribose) (PAR), which is synthesized by PARP family proteins during the poly ADP-ribosylation cycle. We previously reported that the PARG inhibitor PDD00017273 suppressed osteoclast differentiation through PAR accumulation in RANKL-stimulated RAW264 cells. However, the molecular mechanisms of osteoclast differentiation under PARG inhibition remain unclear, and elucidation of the regulatory mechanisms may contribute to the development of novel therapeutic strategies for metabolic bone diseases associated with excessive activation of osteoclasts. In the present study, we investigated the molecular mechanisms whereby PDD00017273 suppresses osteoclast differentiation. RNA-seq and pathway analyses revealed enrichment of oxidative stress- and redox regulation-related pathways, and an ATAC-seq analysis identified enrichment of the NRF2-binding motif in PDD00017273-treated RAW264 cells compared with DMSO-treated control cells. Pharmacological inhibition of NRF2 partially restored the osteoclast formation suppressed by PDD00017273. Under these conditions, the expression levels of NRF2-regulated genes were suppressed, while the expression levels of osteoclast marker genes were upregulated. Taken together, the present findings suggest that PAR accumulation via PARG inhibition suppresses osteoclast differentiation through NRF2 activation, indicating that PAR metabolism plays an important role in osteoclast differentiation.
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BibTeX
@article{sasaki2026parg,
title = {{PARG inhibition suppresses osteoclast differentiation through transcriptional activation of an NRF2-dependent pathway}},
author = {Yuka Sasaki and Ryusuke Nakatsuka and Ryoji Taniguchi and Amane Inoue and Mitsuko Masutani and Tadashige Nozaki},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0361101},
url = {https://doi.org/10.1371/journal.pone.0361101},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PARG inhibition suppresses osteoclast differentiation through transcriptional activation of an NRF2-dependent pathway
AU - Yuka Sasaki
AU - Ryusuke Nakatsuka
AU - Ryoji Taniguchi
AU - Amane Inoue
AU - Mitsuko Masutani
AU - Tadashige Nozaki
PY - 2026
DA - 2026/10/26
JO - PLOS One
DO - 10.1371/journal.pone.0361101
UR - https://doi.org/10.1371/journal.pone.0361101
AB - Poly (ADP-ribose) glycohydrolase (PARG) is the main enzyme responsible for degrading poly (ADP-ribose) (PAR), which is synthesized by PARP family proteins during the poly ADP-ribosylation cycle. We previously reported that the PARG inhibitor PDD00017273 suppressed osteoclast differentiation through PAR accumulation in RANKL-stimulated RAW264 cells. However, the molecular mechanisms of osteoclast differentiation under PARG inhibition remain unclear, and elucidation of the regulatory mechanisms may contribute to the development of novel therapeutic strategies for metabolic bone diseases associated with excessive activation of osteoclasts. In the present study, we investigated the molecular mechanisms whereby PDD00017273 suppresses osteoclast differentiation. RNA-seq and pathway analyses revealed enrichment of oxidative stress- and redox regulation-related pathways, and an ATAC-seq analysis identified enrichment of the NRF2-binding motif in PDD00017273-treated RAW264 cells compared with DMSO-treated control cells. Pharmacological inhibition of NRF2 partially restored the osteoclast formation suppressed by PDD00017273. Under these conditions, the expression levels of NRF2-regulated genes were suppressed, while the expression levels of osteoclast marker genes were upregulated. Taken together, the present findings suggest that PAR accumulation via PARG inhibition suppresses osteoclast differentiation through NRF2 activation, indicating that PAR metabolism plays an important role in osteoclast differentiation.
SN - 1932-6203
ER -