4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta.
Ivan DuranJennifer ZiebaFabiana CsukasiJorge H MartinDavis WachtellMaya BaradBrian DawsonBohumil FafilekChristina M JacobsenCatherine G AmbroseDaniel H CohnPavel KrejciBrendan H LeeDeborah KrakowPublished in: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (2022)
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).
Keyphrases
- binding protein
- endoplasmic reticulum
- bone mineral density
- transcription factor
- mouse model
- soft tissue
- bone loss
- bone regeneration
- risk factors
- type diabetes
- combination therapy
- metabolic syndrome
- physical activity
- clinical trial
- replacement therapy
- diffuse large b cell lymphoma
- high resolution
- machine learning
- protein kinase
- dna damage
- smoking cessation
- lipopolysaccharide induced
- early onset
- oxidative stress
- dna methylation
- small molecule
- insulin resistance
- weight loss
- postmenopausal women
- optical coherence tomography
- drug induced
- deep learning
- atrial fibrillation
- dna binding
- genome wide identification