Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model.
Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model.
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DOI：
10.1016/j.mce.2015.12.005
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发表时间：
2016-02-15
影响因子：
4.1
通讯作者：
Fulzele S
中科院分区：
文献类型：
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作者：
Bhatta A;Sangani R;Kolhe R;Toque HA;Cain M;Wong A;Howie N;Shinde R;Elsalanty M;Yao L;Chutkan N;Hunter M;Caldwell RB;Isales C;Caldwell RW;Fulzele S
均衡饮食对健康发育和预防肌肉骨骼相关疾病至关重要。众所周知，脂肪含量高的饮食会导致肥胖、糖尿病和许多其他疾病。我们的小组和其他人以前曾报道，尿素循环酶的活性参与糖尿病诱导的血管功能失调，由于减少一氧化氮的形成。我们假设糖尿病也可能升高骨和骨髓中的β-淀粉酶活性，这可能导致骨相关并发症。为了测试这一点，我们确定了糖尿病对骨和骨髓基质细胞（BMSC）中的β-淀粉酶表达和活性的影响。我们证明，辅酶1是丰富的存在于骨和骨髓基质细胞。我们还证明，在HFHS饮食和链脲佐菌素（STZ）诱导的糖尿病模型中，骨和骨髓中的β-淀粉酶活性和表达上调。HFHS饮食下调了健康骨代谢标志物（BMP 2、COL-1、ALP和RUNX 2）的表达，并降低了骨矿物质密度、骨体积和骨小梁厚度。然而，使用β-淀粉酶抑制剂（ABH）治疗可以预防这些糖尿病骨相关并发症。体外研究表明，高糖处理增加了BMSCs的过氧化物酶活性，减少了一氧化氮的产生。这些作用被逆转的治疗与一个酶抑制剂（ABH）。我们的研究提供的证据表明，L-精氨酸代谢的失调在HFHS饮食诱导的糖尿病并发症中起着至关重要的作用，这些并发症可以通过使用精氨酸酶抑制剂治疗来预防。在疾病中调节L-精氨酸代谢可能为骨质疏松症和其他肌肉骨骼相关疾病提供新的治疗方法。
A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of L-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of L-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases.