ARG2 drives osteoblast senescence by repressing mitophagy via the IκB–NF-κB–TXN2 signaling axis: implications for age-associated osteoporosis

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.