Prmt6 Deficiency Drives Osteoblast Senescence Promoting Age-Related Osteoporosis via Epigenetic Remodelling of the H3R2me2a/Sting/Ifitm3 Pathway

Abstract

Protein arginine methyltransferase 6 (Prmt6), an epigenetic regulator, plays an unclear role in bone homeostasis and osteoblast senescence. In this study, we employed Western blot, qPCR, immunofluorescence, SA-β-Gal staining, and RNA-seq to systematically investigate the regulatory mechanism of the Prmt6/H3R2me2a/Sting/Ifitm3 axis in osteoblast senescence, and further validated the association of relevant molecules with osteoporosis at the animal level using immunohistochemistry and micro-CT. Our results showed that Prmt6 deficiency led to bone loss and induced osteoblast senescence in mice. Mechanistically, Prmt6 ablation was accompanied by reduced H3R2me2a modification and increased chromatin accessibility at the Sting promoter, suggesting that this histone mark may restrict local chromatin opening, thereby triggering sustained activation of the Sting pathway and marked upregulation of its classical downstream target gene Ifitm3. Functional experiments confirmed that inhibiting Sting or knocking down Ifitm3 effectively alleviated the senescent phenotype of osteoblasts. Consistently, in aged bone tissues, Prmt6 and H3R2me2a expression were decreased, while Sting and Ifitm3 levels were elevated. Collectively, this study reveals a previously unreported Prmt6/H3R2me2a/Sting/Ifitm3 signalling axis that maintains osteoblast homeostasis by constraining excessive activation of the Sting/Ifitm3 axis via epigenetic repressive modifications, offering a novel target for epigenetic intervention in osteoporosis.