4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long-bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4-phenylbutiric acid (4-PBA), an established chemical chaperone, to determine if treatment of Aga2(+/-) mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2(+/-) osteoblasts show increased protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4-PBA. The in vivo data demonstrate that a postweaning 5-week 4-PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone-derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/-enhancer-binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2(+/-) mice resulted in increased severity of the Aga2(+/-) phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Automated summary

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and deformities. Endoplasmic reticulum (ER) stress has been identified as a contributing factor to OI pathogenesis. In this study, treatment with the chemical chaperone 4-phenylbutiric acid (4-PBA) was found to alleviate the phenotype of OI in mice, leading to improved growth, bone density, and reduced ER stress markers.