Carrasco Jeldres, Margarita E

Abstract Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator Polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in wild-type cells. Here we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2+/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.