4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta.
4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta.
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DOI：
10.1002/jbmr.4501
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发表时间：
2022-04
影响因子：
6.2
通讯作者：
Krakow, Deborah
中科院分区：
文献类型：
--
作者：
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
成骨不全症（OI）是一种遗传异质性疾病，最常见的原因是I型前胶原基因COL1A1或COL1A2突变的杂合性。这种疾病的特点是骨骼脆弱，导致骨折发生率增加和长骨畸形。虽然成骨不全有多种机制，但内质网（ER）应激作为细胞对胶原蛋白运输缺陷的反应，正在成为成骨不全发病的一个因素。在这里，我们使用4‐苯基丁酸（4‐PBA），一种已建立的化学伴侣，来确定是否治疗Aga2 +/−小鼠，一个由Col1a1结构突变引起的中度严重OI模型，可以减弱表型。在体外，Aga2 +/−成骨细胞显示出蛋白激酶RNA样内质网激酶（PERK）激活蛋白水平升高，这在4‐PBA处理后得到改善。体内数据表明，断奶后5周的4 - PBA治疗增加了总体长和体重，降低了骨折发生率，增加了股骨体积分数（BV/TV），增加了皮质厚度。这些发现与体内内质网应激标记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记轻链3A/B （LC3A/B）水平升高有关。基因消融Aga2 +/−小鼠的CHOP导致Aga2 +/−表型的严重程度增加，这表明体外治疗后观察到的CHOP减少是内质网应激减少的结果而不是原因。这些发现表明，化学伴侣可能作为与内质网应激相关的成骨不全的辅助治疗。©2022作者。由Wiley期刊有限责任公司代表美国骨与矿物研究协会（ASBMR）出版的骨与矿物研究杂志。
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).
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影响因子：
3.5
作者：
Gioia R;Tonelli F;Ceppi I;Biggiogera M;Leikin S;Fisher S;Tenedini E;Yorgan TA;Schinke T;Tian K;Schwartz JM;Forte F;Wagener R;Villani S;Rossi A;Forlino A
通讯作者：
Forlino A
影响因子：
3.5
作者：
Brose, Rebecca Deering;Shin, Gloria;Smith, Kirby D.
通讯作者：
Smith, Kirby D.
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
6.2
作者：
Glorieux, Francis H.;Devogelaer, Jean-Pierre;Winkle, Peter J.
通讯作者：
Winkle, Peter J.
影响因子：
3
作者：
Iannitti T;Palmieri B
通讯作者：
Palmieri B