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

• Published in: Journal of bone and mineral research Vol. 37; no. 4; pp. 675 - 686
• Main Authors: Duran, Ivan, Zieba, Jennifer, Csukasi, Fabiana, Martin, Jorge H., Wachtell, Davis, Barad, Maya, Dawson, Brian, Fafilek, Bohumil, Jacobsen, Christina M., Ambrose, Catherine G., Cohn, Daniel H., Krejci, Pavel, Lee, Brendan H., Krakow, Deborah
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-04-2022; Wiley Subscription Services, Inc
• Subjects: 4‐PBA; Activating transcription factor 4; Aga2; Animals; Bip; Body length; bone; Butylamines; Chop; Collagen; Collagen (type I); Collagen Type I - metabolism; Disease Models, Animal; Endoplasmic reticulum; ER stress; Fractures; Heterozygosity; Kinases; Long bone; Mice; Molecular Chaperones - metabolism; Mutation; Osteoblasts - metabolism; Osteogenesis; Osteogenesis imperfecta; Osteogenesis Imperfecta - drug therapy; Osteogenesis Imperfecta - genetics; Osteogenesis Imperfecta - metabolism; Phenotype; Phenotypes; Procollagen; Protein kinase; Proteins; 4-PBA; Chop; Aga2; Bip; ER stress; bone; osteogenesis imperfecta
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.4501

ABSTRACT
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. © 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).