H3K27 Acetylation-driven IGF2BP2 Mutates during the Aging of MSCs, thereby Influencing Osteogenic Differentiation and Bone Aging

Aging-related bone loss is closely linked to mesenchymal stem cell (MSC) senescence, but the underlying epigenetic mechanisms remain unclear. Here, the role of histone H3 lysine 27 acetylation (H3K27ac) and its downstream target IGF2BP2 in MSC aging are investigated. Integrated ChIP-seq and RNA-seq analyses revealed diminished H3K27ac levels in aged murine bone marrow-MSCs (BM-MSCs), accompanied by reduced IGF2BP2 expression. Functional studies demonstrated that both knockdown and overexpression of IGF2BP2 mitigated senescence phenotypes in hydrogen peroxide- and etoposide-induced models. The mutation frequency of H65Q, a key point mutation in IGF2BP2, exhibited variations according to age and sex, and enhanced its binding to <i>Hmga1</i> mRNA, stabilizing HMGA1 and activating the p53/p21 pathway to accelerate senescence. HMGA1 interacted with p53 to modulate DNA damage responses. Pharmacological inhibition of IGF2BP2 using CWI1-2 alleviated MSC senescence <i>in vitro</i> and enhanced bone regeneration in aged mice by improving bone mineral density and trabecular microstructure. These findings establish the H3K27ac-IGF2BP2-HMGA1 axis as a central regulator of bone aging and propose CWI1-2 as a promising therapeutic agent for age-related osteoporosis.