Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus
Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus
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DOI：
10.1210/en.2007-1408
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发表时间：
2008-04-01
期刊：
影响因子：
4.8
通讯作者：
Thrailkill, Kathryn M.
中科院分区：
文献类型：
--
作者：
Fowlkes, John L.;Bunn, R. Clay;Thrailkill, Kathryn M.
1型糖尿病与许多骨骼健康障碍有关，这些疾病部分依赖于动态骨形成。牵张成骨的小鼠模型被用来研究链脲佐菌素诱导的糖尿病和胰岛素治疗对骨形成和成骨细胞生成的后果。与对照组小鼠相比，糖尿病小鼠牵张间隙内和周围的新骨形成减少，脂肪形成增加。虽然胰岛素治疗恢复了非糖尿病对照小鼠的骨形成水平，但未能显著降低脂肪生成。在未经治疗的1型糖尿病患者中，在从头骨形成过程中发生的分子事件发生了改变，但在胰岛素治疗后又恢复了，因此我们对这些分子事件进行了检查，以阐明可能导致糖尿病性骨疾病的特定成骨基因。通过基因芯片和定量RT-PCR分析牵张间隙中的RNA，以寻找感兴趣的成骨基因。Runt相关转录因子2（RUNX 2）和几个RUNX 2靶基因，包括基质金属蛋白酶-9，Akp 2，整合素结合唾液蛋白，Dmp 1，Col 1a 2，Phex，Vdr，骨钙素和osterix，在胰岛素缺乏，高血糖糖尿病动物中均显著下调;然而，糖尿病动物的胰岛素治疗显著恢复其表达。骨形态发生蛋白-2、具有PDZ结合基序的转录共激活因子和TWIST 2（RUNX 2的所有重要调节因子）的表达不受糖尿病条件的影响，这表明成骨缺陷存在于RUNX 2表达及其活性水平。总之，这些数据表明，胰岛素和/或血糖状态可以调节体内骨生成，全身胰岛素治疗可以在很大程度上挽救组织和分子水平的糖尿病骨表型。
Type 1 diabetes mellitus is associated with a number of disorders of skeletal health, conditions that rely, in part, on dynamic bone formation. A mouse model of distraction osteogenesis was used to study the consequences of streptozotocin-induced diabetes and insulin treatment on bone formation and osteoblastogenesis. In diabetic mice compared with control mice, new bone formation was decreased, and adipogenesis was increased in and around, respectively, the distraction gaps. Although insulin treatment restored bone formation to levels observed in nondiabetic control mice, it failed to significantly decrease adipogenesis. Molecular events altered during de novo bone formation in untreated type 1 diabetes mellitus, yet restored with insulin treatment were examined so as to clarify specific osteogenic genes that may contribute to diabetic bone disease. RNA from distraction gaps was analyzed by gene microarray and quantitative RT-PCR for osteogenic genes of interest. Runt-related transcription factor 2 (RUNX2), and several RUNX2 target genes, including matrix metalloproteinase-9, Akp2, integrin binding sialoprotein, Dmp1, Col1a2, Phex, Vdr, osteocalcin, and osterix, were all significantly down-regulated in the insulin-deficient, hyperglycemic diabetic animals; however, insulin treatment of diabetic animals significantly restored their expression. Expression of bone morphogenic protein-2, transcriptional coactivator with PDZ-binding motif, and TWIST2, all important regulators of RUNX2, were not impacted by the diabetic condition, suggesting that the defect in osteogenesis resides at the level of RUNX2 expression and its activity. Together, these data demonstrate that insulin and/or glycemic status can regulate osteogenesis in vivo, and systemic insulin therapy can, in large part, rescue the diabetic bone phenotype at the tissue and molecular level.