{"doi":"10.1002/jbmr.4501","title":"4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta","abstract":"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).","journal":"Journal of Bone and Mineral Research","year":2020,"id":64156,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":20890,"name":"Jennifer Zieba","orcid":"0000-0003-1650-1830","position":1,"is_corresponding":false},{"id":339391,"name":"Fabiana Csukasi","orcid":"0000-0001-8242-1228","position":2,"is_corresponding":false},{"id":339392,"name":"Jorge Martı́n","orcid":"0000-0002-6312-7637","position":3,"is_corresponding":false},{"id":339393,"name":"Davis Wachtell","orcid":"0000-0002-8369-3919","position":4,"is_corresponding":false},{"id":339394,"name":"Maya Barad","orcid":"0000-0003-2577-9236","position":5,"is_corresponding":false},{"id":297071,"name":"Brian Dawson","orcid":null,"position":6,"is_corresponding":false},{"id":339395,"name":"Bohumil Fafílek","orcid":"0000-0002-3869-7937","position":7,"is_corresponding":false},{"id":289377,"name":"Christina M. Jacobsen","orcid":"0009-0009-7326-5062","position":8,"is_corresponding":false},{"id":339396,"name":"Catherine G. Ambrose","orcid":"0000-0002-3866-0683","position":9,"is_corresponding":false},{"id":339397,"name":"Daniel H. Cohn","orcid":"0000-0003-0388-4457","position":10,"is_corresponding":false},{"id":339398,"name":"Pavel Krejčı́","orcid":"0000-0003-0618-9134","position":11,"is_corresponding":false},{"id":249412,"name":"Brendan Lee","orcid":"0000-0001-8573-4211","position":12,"is_corresponding":false},{"id":339399,"name":"Deborah Krakow","orcid":"0000-0001-9906-4968","position":13,"is_corresponding":false},{"id":339390,"name":"Iván Durán","orcid":"0000-0001-6097-0402","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T21:12:32.635050Z","pmid":"34997935","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}