Grx2 deficiency accelerates BMSC senescence and senile osteoporosis via CD36 S-glutathionylation.

rationaleSenile osteoporosis (SOP) is driven largely by bone marrow mesenchymal stem cell (BMSC) senescence and mitochondrial dysfunction. S-glutathionylation is an important redox modification regulating mitochondrial homeostasis, yet its role in skeletal aging remains unclear. The objective of this study is to systematically investigate the role of Grx2 deficiency-mediated CD36 S-glutathionylation in BMSC senescence and SOP development.

methodsGrx2, p53, and p21 expression in human and mouse BMSCs were analyzed by immunohistochemistry (IHC), western blotting (WB), and polymerase chain reaction (PCR). Aging-related and ovariectomy-induced osteoporosis models were established in Grx2

resultsGrx2 deficiency, in both male and ovariectomized female mice, accelerates bone loss, inhibits osteoblast formation without altering osteoclast function, and exacerbates BMSC senescence. Through integrated transcriptomic and S-glutathionylated proteomic analysis, we identified the fatty acid transporter CD36 as a critical downstream target of Grx2. Notably, Grx2 deficiency markedly increases the S-glutathionylation of CD36, which not only enhances its fatty acid uptake capacity, leading to the accumulation of toxic lipid metabolites and oxidative damage, but also impairs mitochondrial energy metabolism by inhibiting the PI3K/AKT signaling pathway. Overexpression of Grx2 or the C272S mutation in CD36, which disrupts its S-glutathionylation, can break this harmful cycle and inhibit BMSC senescence.

conclusionsGrx2 deficiency-mediated CD36 S-glutathionylation drives BMSC senescence and SOP, providing new insight into the redox regulatory mechanisms underlying skeletal aging.