β-Catenin mediates glucose-dependent insulinotropic polypeptide increases in lysyl oxidase expression in osteoblasts.
β-Catenin mediates glucose-dependent insulinotropic polypeptide increases in lysyl oxidase expression in osteoblasts.
复制标题
β-连环蛋白介导葡萄糖依赖性促胰岛素多肽增加成骨细胞中赖氨酰氧化酶的表达
DOI：
10.1016/j.bonr.2021.101063
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发表时间：
2021-06
期刊：
影响因子：
2.5
通讯作者：
Trackman PC
中科院分区：
文献类型：
--
作者：
Daley EJ;Trackman PC
成骨细胞赖氨酰氧化酶(LOX)是一种受葡萄糖依赖的促胰岛素多肽(GIP)强烈上调的mRNA和蛋白质。LOX是胶原蛋白成熟所必需的，在1型糖尿病小鼠模型中，LOX的表达显著下调，这与人类和小鼠糖尿病骨骼疾病中已知的低胶原交联和骨质量差的情况一致。胃肠道激素是一种胃激素，在摄取营养物质后由肠道释放，然后刺激胰腺中的β细胞释放胰岛素。GIP直接对成骨细胞和骨进行合成代谢，而肠源性多巴胺减弱了GIP对成骨细胞合成代谢途径的影响，包括LOX的表达。GIP对LOX表达的刺激依赖于cAMP水平和蛋白激酶A活性的增加，这与GIP受体是G蛋白偶联受体的事实一致。然而，导致LOX表达增加的下游信号事件仍未被探索。在这里，我们提供了β-连环蛋白介导的GIP信号增加LOX表达的证据。此外，我们还在LOX启动子中确定了LOX上调GIP所需的TCF/LEF元件。这些发现将对设计潜在的治疗方法来解决糖尿病骨疾病中LOX产生不足的问题具有重要意义，因为它指出了探索在糖尿病条件下刺激成骨细胞中的β-连环蛋白信号作为潜在治疗策略的重要性。
Osteoblast lysyl oxidase (LOX) is a strongly up-regulated mRNA and protein by the glucose-dependent insulinotropic polypeptide (GIP). LOX is critically required for collagen maturation, and was shown to be dramatically down-regulated in a mouse model of type 1 diabetes, consistent with known low collagen cross-linking and poor bone quality in diabetic bone disease in humans and in mouse models. GIP is a gastric hormone released by the gut upon consumption of nutrients, which then stimulates insulin release from β-cells in the pancreas. GIP is directly anabolic to osteoblasts and to bone, while gut-derived dopamine attenuates effects of GIP on osteoblast anabolic pathways, including LOX expression. GIP-stimulation of LOX expression was shown to be dependent on increased cAMP levels and protein kinase A activity, consistent with the fact that GIP receptors are G protein coupled receptors. Downstream signaling events resulting in increased LOX expression remain, however, unexplored. Here we provide evidence for β-catenin mediation of signaling from GIP to increase LOX expression. Moreover, we have identified a TCF/LEF element in the Lox promoter that is required for GIP-upregulation of LOX. These findings will be of importance in designing potential therapeutic approaches to address deficient LOX production in diabetic bone disease by pointing to the importance of exploring strategies to stimulate β-catenin signaling in osteoblasts under diabetic conditions as potential therapeutic strategies.
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影响因子：
4.2
作者：
Alsofi L;Daley E;Hornstra I;Morgan EF;Mason ZD;Acevedo JF;Word RA;Gerstenfeld LC;Trackman PC
通讯作者：
Trackman PC
影响因子：
4.1
作者：
Mieczkowska, Aleksandra;Irwin, Nigel;Mabilleau, Guillaume
通讯作者：
Mabilleau, Guillaume
影响因子：
15.9
作者：
NAUCK, MA;HEIMESAAT, MM;CREUTZFELDT, W
通讯作者：
CREUTZFELDT, W
影响因子：
5.6
作者：
Hong, HH;Pischon, N;Trackman, PC
通讯作者：
Trackman, PC
影响因子：
16.6
作者：
Killion EA;Chen M;Falsey JR;Sivits G;Hager T;Atangan L;Helmering J;Lee J;Li H;Wu B;Cheng Y;Véniant MM;Lloyd DJ
通讯作者：
Lloyd DJ