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).

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Human Genetics David Geffen School of Medicine at University of California at Los Angeles Los Angeles CA USA

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA

Department of Molecular Cell and Developmental Biology University of California at Los Angeles Los Angeles CA USA

Department of Obstetrics and Gynecology David Geffen School of Medicine at University of California at Los Angeles Los Angeles CA USA

Department of Orthopaedic Surgery David Geffen School of Medicine at University of California at Los Angeles Los Angeles CA USA

Department of Orthopaedic Surgery University of Texas Health Science Center at Houston Houston TX USA

Department of Pediatrics David Geffen School of Medicine at University of California at Los Angeles Los Angeles CA USA

Department of Pediatrics Harvard Medical School Boston MA USA

Divisions of Endocrinology and Genetics and Genomics Boston Children's Hospital Boston MA USA

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Laboratory of Bioengineering and Tissue Regeneration Málaga Spain

Networking Biomedical Research Center in Bioengineering Biomaterials and Nanomedicine Málaga Spain

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