Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy.
Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy.
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在主要成骨的鼠模型中，成骨细胞生成受损：成骨的新靶标不完美的药物治疗。
DOI：
10.1002/stem.1107
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发表时间：
2012-07
期刊：
影响因子：
5.2
通讯作者：
Forlino, Antonella
中科院分区：
文献类型：
--
作者：
Gioia, Roberta;Panaroni, Cristina;Besio, Roberta;Palladini, Giovanni;Merlini, Giampaolo;Giansanti, Vincenzo;Scovassi, Ivana A.;Villani, Simona;Villa, Isabella;Villa, Anna;Vezzoni, Paolo;Tenni, Ruggero;Rossi, Antonio;Marini, Joan C.;Forlino, Antonella
关键词：
骨疾病临床表型的分子基础通常与异常的细胞外基质结构和/或性质相关。最近，细胞功能障碍已被确定为伴随的致病因素，并且越来越多的注意力集中在干细胞分化上。经典的成骨发育不良（OI）是遗传性骨发育不良的原型：它具有显性遗传传递，由编码I型胶原蛋白（骨中最丰富的蛋白质）的基因突变引起。使用Brt 1小鼠，一种中重度显性OI的良好表征的敲入模型，我们证明了骨髓祖细胞向成骨细胞分化的损伤。在突变型间充质干细胞（MSC）中，早期（Runx 2和Sp 7）和晚期（Col 1a 1和Ibsp）成骨细胞标志物的表达相对于野生型（WT）显著降低。相反，与WT相比，突变MSC产生更多的集落形成单位-脂肪细胞，每个集落具有更多的脂肪细胞，并且每个细胞的甘油三酯滴的数量和大小增加。自噬上调也被证明在突变型成人间充质干细胞分化成骨谱系的内质网应激的结果，由于突变型胶原蛋白滞留。用蛋白酶体抑制剂硼替佐米治疗Brt 1小鼠改善了体外成骨细胞分化和体内骨特性，如分别通过长骨上的集落形成单位成骨细胞测定和外周定量计算机断层扫描分析所证明的。这是第一个报告受损的MSC分化成骨细胞在OI，它确定了一个新的潜在目标的药物治疗的疾病。
The molecular basis underlying the clinical phenotype in bone diseases is customarily associated with abnormal extracellular matrix structure and/or properties. More recently, cellular malfunction has been identified as a concomitant causative factor and increased attention has focused on stem cells differentiation. Classic osteogenesis imperfecta (OI) is a prototype for heritable bone dysplasias: it has dominant genetic transmission and is caused by mutations in the genes coding for collagen I, the most abundant protein in bone. Using the Brtl mouse, a well-characterized knockin model for moderately severe dominant OI, we demonstrated an impairment in the differentiation of bone marrow progenitor cells toward osteoblasts. In mutant mesenchymal stem cells (MSCs), the expression of early (Runx2 and Sp7) and late (Col1a1 and Ibsp) osteoblastic markers was significantly reduced with respect to wild type (WT). Conversely, mutant MSCs generated more colony-forming unit-adipocytes compared to WT, with more adipocytes per colony, and increased number and size of triglyceride drops per cell. Autophagy upregulation was also demonstrated in mutant adult MSCs differentiating toward osteogenic lineage as consequence of endoplasmic reticulum stress due to mutant collagen retention. Treatment of the Brtl mice with the proteasome inhibitor Bortezomib ameliorated both osteoblast differentiation in vitro and bone properties in vivo as demonstrated by colony-forming unit-osteoblasts assay and peripheral quantitative computed tomography analysis on long bones, respectively. This is the first report of impaired MSC differentiation to osteoblasts in OI, and it identifies a new potential target for the pharmacological treatment of the disorder.
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影响因子：
5.8
作者：
Harslof, Torben;Wamberg, Louise;Langdahl, Bente L.
通讯作者：
Langdahl, Bente L.
影响因子：
6.2
作者：
Chen, XD;Shi, ST;Young, MF
通讯作者：
Young, MF
影响因子：
15.9
作者：
Crossno, Joseph T., Jr.;Majka, Susan M.;Klemm, Dwight J.
通讯作者：
Klemm, Dwight J.
DOI：
10.1073/pnas.0903269107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Kilian, Kristopher A.;Bugarija, Branimir;Mrksich, Milan
通讯作者：
Mrksich, Milan
影响因子：
3.1
作者：
Heider, Ulrike;Kaiser, Martin;Sezer, Orhan
通讯作者：
Sezer, Orhan