|
|||||
|
|
4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta |
|
| Authors: | Ivan Duran Jennifer Zieba Fabiana Csukasi Jorge H. Martin Davis Wachtell Maya Barad Brian Dawson Bohumil Fafilek Christina M. Jacobsen Catherine G. Ambrose Daniel H. Cohn Pavel Krejci Brendan H. Lee Deborah Krakow |
| Affiliation: | 1. Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, University of Málaga, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain ID and JZ are joint first authors. Contribution: Conceptualization, Investigation, Methodology, Visualization, Writing - original draft;2. Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA ID and JZ are joint first authors. Contribution: Conceptualization, Investigation, Methodology, Visualization, Writing - original draft, Writing - review & editing;3. Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, University of Málaga, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain Contribution: Investigation;4. Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA Contribution: Investigation;5. Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA Contribution: Investigation, Writing - original draft;6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Contribution: Investigation;7. Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic Contribution: Investigation;8. Divisions of Endocrinology and Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA Department of Pediatrics, Harvard Medical School, Boston, MA, USA Contribution: Resources;9. Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA Contribution: Investigation;10. Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA Department of Molecular Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, CA, USA;11. Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic Contribution: Conceptualization, Resources, Writing - review & editing;12. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;13. Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA |
| 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). |
| Keywords: | osteogenesis imperfecta Aga2 bone 4-PBA ER stress Chop−/− Bip+/− |