Loss of Iroquois homeobox transcription factors 3 and 5 in osteoblasts disrupts cranial mineralization.
Loss of Iroquois homeobox transcription factors 3 and 5 in osteoblasts disrupts cranial mineralization.
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DOI：
10.1016/j.bonr.2016.02.005
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发表时间：
2016-12
期刊：
影响因子：
2.5
通讯作者：
Hsiao EC
中科院分区：
文献类型：
--
作者：
Cain CJ;Gaborit N;Lwin W;Barruet E;Ho S;Bonnard C;Hamamy H;Shboul M;Reversade B;Kayserili H;Bruneau BG;Hsiao EC
颅骨畸形是围产期发病率和死亡率的一个重要原因。易洛魁人同源盒转录因子（IRX）在骨组织形成早期表达，促进骨骼的形成和矿化。缺乏Irx 5的小鼠看起来非常正常，这表明易洛魁家族中的冗余。然而，在小鼠中Irx 3和Irx 5两者的整体缺失导致显著的骨骼畸形和来自心脏缺陷的胚胎致死。在这里，我们使用Osx-Cre研究Irx 3和Irx 5的骨特异性功能，以驱动Irx 5 −/−小鼠中的成骨细胞谱系特异性Irx 3缺失。虽然我们发现Osx-Cre转基因单独也可以影响颅面矿化，但新生的Irx 3flox/flox/Irx 5 −/−/Osx-Cre+小鼠在顶骨、顶间骨和额骨中表现出额外的矿化缺陷，骨缝扩大，成骨基因的颅骨表达减少。新生儿软骨内长骨基本上不受影响，但我们观察到Irx 3flox/flox/Irx 5 −/−/Osx-Cre+小鼠3-4周龄骨矿物质含量显著降低。我们的研究结果表明，IRX 3和IRX 5可以共同调节特定颅骨的矿化。我们的研究结果还提供了深入了解骨骼变化和矿化缺陷的原因，在Hamamy综合征患者携带IRX 5突变。成骨细胞特异性Irx 3和Irx 5缺失导致新生小鼠顶骨、顶骨间骨和额骨矿化缺陷3-4一周大的Irx 3flox/flox/Irx 5 −/−/Osx-Cre+小鼠显示出与IRX 5突变的Hamamy综合征患者相似的骨脆性。Osx-Cre转基因单独导致早期骨矿化表型，随后恢复。
Cranial malformations are a significant cause of perinatal morbidity and mortality. Iroquois homeobox transcription factors (IRX) are expressed early in bone tissue formation and facilitate patterning and mineralization of the skeleton. Mice lacking Irx5 appear grossly normal, suggesting that redundancy within the Iroquois family. However, global loss of both Irx3 and Irx5 in mice leads to significant skeletal malformations and embryonic lethality from cardiac defects. Here, we study the bone-specific functions of Irx3 and Irx5 using Osx-Cre to drive osteoblast lineage–specific deletion of Irx3 in Irx5−/− mice. Although we found that the Osx-Cre transgene alone could also affect craniofacial mineralization, newborn Irx3flox/flox/Irx5−/−/Osx-Cre+ mice displayed additional mineralization defects in parietal, interparietal, and frontal bones with enlarged sutures and reduced calvarial expression of osteogenic genes. Newborn endochondral long bones were largely unaffected, but we observed marked reductions in 3–4-week old bone mineral content of Irx3flox/flox/Irx5−/−/Osx-Cre+ mice. Our findings indicate that IRX3 and IRX5 can work together to regulate mineralization of specific cranial bones. Our results also provide insight into the causes of the skeletal changes and mineralization defects seen in Hamamy syndrome patients carrying mutations in IRX5. Osteoblast-specific deletion of Irx3 and Irx5 causes mineralization defects in parietal, interparietal, and frontal bones of newborn mice. 3–4 week old Irx3flox/flox/Irx5−/−/Osx-Cre+ mice show similar bone fragility to Hamamy syndrome patients who have mutations in IRX5. Osx-Cre transgene alone causes an early bone mineralization phenotype that recovers later.