GLP-1受体激动剂通过IRS-1/PI3K/Akt信号通路调节骨代谢

Osteoporosis (OP) is a common bone metabolic disease. The essence of osteoporosis is imbalance of bone formation and absorption during bone remodeling，which is regulated by various factors. Recent studies have showed that glucagon-like peptide-1 (GLP-1) can regulate bone metabolism through various ways. Now one research have found that GLP-1 receptor agonists can inhibit appetite by activating the IRS-1/PI3K/Akt pathway in the hypothalamus. However IRS-1 also plays an important role in bone metabolism. We have been successfully silenced IRS1 gene in MC3T3-E1 cell using Small interfering RNA. Our results showed that IRS-1 short hairpin RNAs can effectively suppress the expression of IRS1, and inhibit the phosphorylation of Akt in IRS1 pathway. So we propose that GLP -1 receptor agonist can regulate bone metabolism through IRS-1 /PI3K/Akt signal pathway. In order to verify this hypothesis, animal and cytological experiments will be done. The successful demonstration of this hypothesis not only provides a new theory for GLP-1 receptor agonist promoting bone formation, but also provides a theoretical support for the treatment of osteoporosis.

骨质疏松（osteoporosis，OP）是一种常见的骨代谢疾病，其本质是骨重建过程中骨形成与骨吸收失衡，这一过程受多种因素调控。近年研究发现胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)可通过多种途径调节骨代谢。新近研究发现 GLP-1受体激动剂在下丘脑可以通过激活IRS-1/PI3K/Akt途径而抑制大鼠摄食，而IRS-1在骨代谢中亦具有重要作用。我们既往成功地应用小RNA干扰技术沉默MC3T3-E1细胞IRS-1基因，研究结果显示：ShRNA可有效抑制IRS-1基因表达，并抑制IRS-1传导途径的Akt磷酸化。因此我们大胆提出假设GLP-1受体激动剂可以通过IRS-1/PI3K/Akt信号通路调节骨代谢。本课题围绕这一假设通过动物和细胞学实验进行验证。该假说的成功论证为GLP-1受体激动剂调节骨代谢找到了新的理论依据。

骨质疏松（osteoporosis，OP）是一种常见的骨代谢疾病，其本质是骨重建过程中骨形成与骨吸收失衡，这一过程受多种因素调控。近年研究发现胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)可通过多种途径调节骨代谢。新近研究发现GLP-1受体激动剂在下丘脑可以通过激活IRS-1/PI3K/Akt途径而抑制大鼠摄食，而IRS-1在骨代谢中亦具有重要作用。我们既往成功地应用小RNA干扰技术沉默MC3T3-E1细胞IRS-1基因，研究结果显示：ShRNA可有效抑制IRS-1基因表达，并抑制IRS-1传导途径的Akt磷酸化。因此我们大胆提出假设GLP-1受体激动剂可以通过IRS-1/PI3K/Akt信号通路调节骨代谢。本研究围绕这一假设通过动物和细胞学实验进行验证，研究表明，Exendin-4可改善OVX大鼠骨微结构、降低骨转换，促进成骨细胞IRS-1蛋白表达，对OVX大鼠具有骨保护作用；Exendin-4可促进前成骨MC3T3-E1细胞增殖、分化和矿化，上调骨形成标志物基因表达量，以及刺激IRS-1表达、激活IRS-1/PI3K/Akt信号通路，进而促进骨形成。该假说的成功论证为GLP-1受体激动剂调节骨代谢找到了新的理论依据。