ARG2 drives osteoblast senescence by repressing mitophagy via the IκB-NF-κB-TXN2 signaling axis: implications for age-associated osteoporosis.
4 affiliations
- 1Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
- 2School of Medicine, Northwest University, Xi'an, Shaanxi 710069, China.
- 3Department of Orthopaedics, Shenmu Hospital, The Affiliated Shenmu Hospital of Northwest University, Guangming Road, Shenmu, China.
- 4Department of Science and Education, Shenmu Hospital, The Affiliated Shenmu Hospital of Northwest University, Shenmu, China.
Abstract
Rationale
Age-associated osteoporosis (AAOP) is characterized by progressive bone loss that can be driven by impaired osteoblast function and increased cellular senescence. However, the molecular mechanisms driving osteoblast senescence during aging remain incompletely understood. In this study, we aim to investigate the role of arginase 2 (ARG2) and its underlying mechanisms in osteoblast senescence and AAOP.Methods
AAOP were assessed in D-galactose-induced aging mice, naturally aged mice, and osteoblast-specific ARG2 knockout mice. In vitro, osteoblast senescence was induced by hydrogen peroxide exposure. Bone phenotypes, cellular senescence, mitochondrial function, and mitophagy were examined using histological, molecular, and imaging techniques. Luciferase reporter assays, co-immunoprecipitation (Co-IP), and pharmacological or genetic approaches were employed for molecular mechanistic investigations.Results
We observed that ARG2 expression was markedly elevated in senescent osteoblasts and aged mice with osteoporosis. Osteoblast-specific deletion of ARG2 alleviated age-related bone loss, improved trabecular bone microarchitecture, and reduced osteoblast senescence in vivo. Mechanistically, ARG2 promoted mitochondrial oxidative stress and impaired mitophagy, as evidenced by inhibition of the PINK1/Parkin/LC3 pathway and accumulation of p62. Furthermore, we revealed that ARG2 activated IκBα/NF-κB signaling, leading to HDAC9-mediated transcriptional repression of thioredoxin 2 (TXN2), a key mitochondrial antioxidant. Restoration of TXN2 expression, antioxidant treatment, or blockade of NF-κB/HDAC9 signaling rescued mitophagy, attenuated osteoblast senescence, and restored osteogenic function. Moreover, pharmacological inhibition of ARG2 using S-(2-boronoethyl)-L-cysteine (BEC) significantly suppressed osteoblast senescence and protected against age-related osteoporosis.Conclusion
ARG2 plays a pivotal role in osteoblast senescence and the development of AAOP by inducing mitochondrial oxidative stress and mitophagy dysfunction through the IκBα/NF-κB/HDAC9/TXN2 signaling axis. Targeting ARG2 may offer a promising therapeutic approach for AAOP prevention and treatment.
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BibTeX
@article{li2026arg2,
title = {{ARG2 drives osteoblast senescence by repressing mitophagy via the IκB-NF-κB-TXN2 signaling axis: implications for age-associated osteoporosis.}},
author = {Jinli Li and Liyao Zhang and Yuanyuan Ren and Junxuan Wang and Pan Zhang and Qianran Shen and Yaqi Wang and Yi Yu and Zi Cheng and Qiang Wang and Haiying Wang and Yuyan Xiong},
journal = {Theranostics},
year = {2026},
month = sep,
doi = {10.7150/thno.129818},
url = {https://europepmc.org/article/MED/42909967},
note = {CC BY},
}
RIS
TY - JOUR
TI - ARG2 drives osteoblast senescence by repressing mitophagy via the IκB-NF-κB-TXN2 signaling axis: implications for age-associated osteoporosis.
AU - Jinli Li
AU - Liyao Zhang
AU - Yuanyuan Ren
AU - Junxuan Wang
AU - Pan Zhang
AU - Qianran Shen
AU - Yaqi Wang
AU - Yi Yu
AU - Zi Cheng
AU - Qiang Wang
AU - Haiying Wang
AU - Yuyan Xiong
PY - 2026
DA - 2026/09/18
JO - Theranostics
DO - 10.7150/thno.129818
UR - https://europepmc.org/article/MED/42909967
AB - Rationale Age-associated osteoporosis (AAOP) is characterized by progressive bone loss that can be driven by impaired osteoblast function and increased cellular senescence. However, the molecular mechanisms driving osteoblast senescence during aging remain incompletely understood. In this study, we aim to investigate the role of arginase 2 (ARG2) and its underlying mechanisms in osteoblast senescence and AAOP.Methods AAOP were assessed in D-galactose-induced aging mice, naturally aged mice, and osteoblast-specific ARG2 knockout mice. In vitro, osteoblast senescence was induced by hydrogen peroxide exposure. Bone phenotypes, cellular senescence, mitochondrial function, and mitophagy were examined using histological, molecular, and imaging techniques. Luciferase reporter assays, co-immunoprecipitation (Co-IP), and pharmacological or genetic approaches were employed for molecular mechanistic investigations.Results We observed that ARG2 expression was markedly elevated in senescent osteoblasts and aged mice with osteoporosis. Osteoblast-specific deletion of ARG2 alleviated age-related bone loss, improved trabecular bone microarchitecture, and reduced osteoblast senescence in vivo. Mechanistically, ARG2 promoted mitochondrial oxidative stress and impaired mitophagy, as evidenced by inhibition of the PINK1/Parkin/LC3 pathway and accumulation of p62. Furthermore, we revealed that ARG2 activated IκBα/NF-κB signaling, leading to HDAC9-mediated transcriptional repression of thioredoxin 2 (TXN2), a key mitochondrial antioxidant. Restoration of TXN2 expression, antioxidant treatment, or blockade of NF-κB/HDAC9 signaling rescued mitophagy, attenuated osteoblast senescence, and restored osteogenic function. Moreover, pharmacological inhibition of ARG2 using S-(2-boronoethyl)-L-cysteine (BEC) significantly suppressed osteoblast senescence and protected against age-related osteoporosis.Conclusion ARG2 plays a pivotal role in osteoblast senescence and the development of AAOP by inducing mitochondrial oxidative stress and mitophagy dysfunction through the IκBα/NF-κB/HDAC9/TXN2 signaling axis. Targeting ARG2 may offer a promising therapeutic approach for AAOP prevention and treatment.
SN - 1838-7640
ER -