Duran Ivan, Zieba Jennifer, Csukasi Fabiana, Martin Jorge H, Wachtell Davis, Barad Maya, Dawson Brian, Fafilek Bohumil, Jacobsen Christina M, Ambrose Catherine G, Cohn Daniel H, Krejci Pavel, Lee Brendan H, Krakow Deborah
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.
J Bone Miner Res. 2022 Apr;37(4):675-686. doi: 10.1002/jbmr.4501. Epub 2022 Jan 28.
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).
成骨不全症（OI）是一种基因异质性疾病，最常见的原因是I型前胶原基因COL1A1或COL1A2发生杂合性突变。该疾病的特征是骨脆性增加，导致骨折发生率升高和长骨畸形。尽管OI有多种发病机制，但作为细胞对有缺陷的胶原蛋白运输的反应，内质网（ER）应激正逐渐成为OI发病机制的一个促成因素。在此，我们使用已证实的化学伴侣4-苯基丁酸（4-PBA）来确定，对Aga2小鼠（由于Col1a1结构突变导致的中度严重OI模型）进行治疗是否可以减轻其表型。在体外，Aga2成骨细胞显示蛋白激酶RNA样内质网激酶（PERK）激活蛋白水平升高，用4-PBA处理后有所改善。体内数据表明，断奶后进行为期5周的4-PBA治疗可增加全身长度和体重，降低骨折发生率，增加股骨骨体积分数（BV/TV），并增加皮质厚度。这些发现与体内证据相关，即内质网应激标志物结合免疫球蛋白蛋白（BiP）、CCAAT/增强子结合蛋白同源蛋白（CHOP）和激活转录因子4（ATF4）的骨源性蛋白水平降低，以及自噬体标志物轻链3A/B（LC3A/B）水平升高。在Aga2小鼠中对CHOP进行基因敲除导致Aga2表型严重程度增加，这表明在体外治疗后观察到的CHOP减少是内质网应激减轻的结果而非原因。这些发现表明，化学伴侣有可能作为与内质网应激相关的OI形式的辅助治疗手段。© 2022作者。《骨与矿物质研究杂志》由威利期刊有限责任公司代表美国骨与矿物质研究协会（ASBMR）出版。
