ArticleBiochimica et biophysica acta. Molecular basis of disease2018
4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion.
Article in Biochimica et biophysica acta. Molecular basis of disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 88 citations in OpenAlex.
- Inhibition of EED enhances osteogenic differentiation and bone formation: a potential therapeutic strategy for osteogenesis imperfecta.JBMR plus · 2026Article
- Collagen secretion and maturation in osteogenesis imperfecta: Systematic review and meta-analysis.Bone reports · 2026Article
- Collagen hybridizing peptide to target in vivo misfolded collagen in OI zebrafish.Scientific reports · 2026Article
- OMICS Profiling Identifies Signatures of Senescence in Osteogenesis Imperfecta Osteoblasts Counteracted by 4-PBA.Journal of cellular and molecular medicine · 2026Article
- A New Perspective on Osteogenesis Imperfecta: From Cellular Mechanisms to the Systemic Impact of Collagen Dysfunction.International journal of molecular sciences · 2026Review
- Molecular drivers of osteogenesis imperfecta: a cellular and extracellular collagen disease.Clinical science (London, England : 1979) · 2025Review
- The Role of Osteoblasts in Phenotypic Variability of Dominant Osteogenesis Imperfecta: Evidence from Patients and Murine Models.International journal of molecular sciences · 2025Article
- Combined antiresorptive and new anabolic drug approach in osteogenesis imperfecta zebrafish models.JBMR plus · 2025Article
- Osteogenesis imperfecta: pathogenesis, classification, and treatment.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2025Review
- Comprehensive Review of Osteogenesis Imperfecta: Current Treatments and Future Innovations.Human gene therapy · 2025Review
- The administration of exogenous HSP47 as a collagen-specific therapeutic approach.JCI insight · 2025Article
- Bone cell differentiation and mineralization in wild-type and osteogenesis imperfecta zebrafish are compromised by per- and poly-fluoroalkyl substances (PFAS).Scientific reports · 2025Article
- Characterization of a Novel Col1a1Calcified tissue international · 2025Article
- Endoplasmic Reticulum Stress Induces ROS Production and Activates NLRP3 Inflammasome Via the PERK-CHOP Signaling Pathway in Dry Eye Disease.Investigative ophthalmology & visual science · 2024Article
- Medical Management for Fracture Prevention in Children with Osteogenesis Imperfecta.Calcified tissue international · 2024Review
- Zebrafish Models for Skeletal and Extraskeletal Osteogenesis Imperfecta Features: Unveiling Pathophysiology and Paving the Way for Drug Discovery.Calcified tissue international · 2024Review
- Update on the Genetics of Osteogenesis Imperfecta.Calcified tissue international · 2024Review
- Extra-Skeletal Manifestations in Osteogenesis Imperfecta Mouse Models.Calcified tissue international · 2024Review
- The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy.Journal of biomedical science · 2024Review
- Efficient Escorting Strategy for Aggregation-Prone Notch EGF Repeats with Sparcl1.Molecules (Basel, Switzerland) · 2024Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
The clinical phenotype in osteogenesis imperfecta (OI) is attributed to the dominant negative function of mutant type I collagen molecules in the extracellular matrix, by altering its structure and function. Intracellular retention of mutant collagen has also been reported, but its effect on cellular homeostasis is less characterized. Using OI patient fibroblasts carrying mutations in the α1(I) and α2(I) chains we demonstrate that retained collagen molecules are responsible for endoplasmic reticulum (ER) enlargement and activation of the unfolded protein response (UPR) mainly through the eukaryotic translation initiation factor 2 alpha kinase 3 (PERK) branch. Cells carrying α1(I) mutations upregulate autophagy, while cells with α2(I) mutations only occasionally activate the autodegradative response. Despite the autophagy activation to face stress conditions, apoptosis occurs in all mutant fibroblasts. To reduce cellular stress, mutant fibroblasts were treated with the FDA-approved chemical chaperone 4-phenylbutyric acid. The drug rescues cell death by modulating UPR activation thanks to both its chaperone and histone deacetylase inhibitor abilities. As chaperone it increases general cellular protein secretion in all patients' cells as well as collagen secretion in cells with the most C-terminal mutation. As histone deacetylase inhibitor it enhances the expression of the autophagic gene Atg5 with a consequent stimulation of autophagy. These results demonstrate that the cellular response to ER stress can be a relevant target to ameliorate OI cell homeostasis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.