Endoplasmic reticulum stress and autophagy as potential therapeutic targets in SERPINF1 mutation-induced type VI...

Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Mutations in the SERPINF1 gene are known to cause a rare, autosomal recessive form of type VI OI. The pathogenic mechanisms underlying type VI OI caused by mutations in the SERPINF1 gene remain unclear.

Clinical data and genetic analysis were obtained from two unrelated families with type VI OI. Functional studies were performed in MC3T3-E1 osteoblast cells transfected with mutant pigment epithelium-derived factor (PEDF) plasmids. Subsequently, the pathogenesis of novel mutations was investigated through analyses of protein expression, subcellular localization, cell apoptosis, endoplasmic reticulum (ER) stress, and degradation pathways.

Three novel mutations in the SERPINF1 gene were identified in two patients with type VI OI. Subsequent validation in MC3T3-E1 cells demonstrated that all three mutant PEDF proteins failed to be properly secreted and instead accumulated abnormally in the ER. Further analysis indicated that mutant PEDF proteins impaired osteoblast differentiation and mineralization, promoted apoptosis, and induced ER stress. Additionally, mutant PEDF protein-induced ER stress was found to alleviate intracellular protein accumulation through ER-associated degradation (ERAD) and autophagy.

This study identifies three novel mutations in the SERPINF1 gene associated with type VI OI, which disrupt PEDF protein secretion and lead to its accumulation in osteoblasts, causing cell apoptosis and ER stress. Cells attempt to mitigate this stress through ERAD and autophagy. These findings reveal a novel pathogenic mechanism in type VI OI and highlight the role of ER stress and autophagy.