Department of Orthopaedics, The 5th People's Hospital of Shanghai Fudan University, Shanghai, China.
Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Bioengineered. 2022 Jan;13(1):431-439. doi: 10.1080/21655979.2021.2008667.
Osteoporosis is a metabolic bone disease commonly observed in the elderly, and its pathogenesis is associated with declined osteogenic differentiation. Osteogenic differentiation could be facilitated by the activation of the AMP-activated protein kinase (AMPK) pathway. Saxagliptin, an anti-diabetic agent with inhibitory effects against dipeptidyl peptidase 4 (DPP-4), has been recently reported to induce the activation of the AMPK pathway. The present study proposes to explore the function and mechanism of Saxagliptin in osteogenic differentiation. Osteogenic differentiation induction medium (ODIM) was utilized to induce osteogenic differentiation in MC3T3-E1 cells. Significantly increased mineral nodule formation, elevated alkaline phosphatase (ALP) activity, and upregulated expression of osteogenic marker genes activating transcription factor-4 (ATF-4), osteopontin (OPN), and type I collagen (Col1) were observed in ODIM-cultured MC3T3-E1 cells, all of which were further enhanced by the introduction of Saxagliptin. The elevated expression level of runt-related transcription factor-2 (Runx-2), an important transcriptional factor involved in the progression of osteogenic differentiation, in ODIM-cultured MC3T3-E1 cells was further promoted by Saxagliptin. The AMPK pathway in ODIM-cultured MC3T3-E1 cells was significantly activated by Saxagliptin, and the functions of Saxagliptin in promoting osteogenic differentiation were abolished by compound C, the inhibitor of the AMPK pathway. Conclusively, Saxagliptin enhanced osteogenic differentiation in MC3T3-E1 cells, dependent on the activation of AMPKα/RUNX-2.
骨质疏松症是一种常见于老年人的代谢性骨病，其发病机制与成骨分化能力下降有关。成骨分化能力可以通过激活 AMP 激活的蛋白激酶（AMPK）通路来促进。沙格列汀是一种具有抑制二肽基肽酶 4（DPP-4）作用的抗糖尿病药物，最近有报道称其可诱导 AMPK 通路的激活。本研究旨在探讨沙格列汀在成骨分化中的作用及其机制。利用成骨诱导培养基（ODIM）诱导 MC3T3-E1 细胞的成骨分化。结果发现，与对照组相比，在 ODIM 培养的 MC3T3-E1 细胞中，矿化结节形成明显增多，碱性磷酸酶（ALP）活性升高，成骨标志物基因激活转录因子 4（ATF-4）、骨桥蛋白（OPN）和 I 型胶原（Col1）的表达上调，而这些作用均被沙格列汀进一步增强。在 ODIM 培养的 MC3T3-E1 细胞中， runt 相关转录因子 2（Runx-2）的表达水平升高，Runx-2 是成骨分化过程中重要的转录因子，而沙格列汀进一步促进了其表达水平的升高。ODIM 培养的 MC3T3-E1 细胞中 AMPK 通路被沙格列汀显著激活，而 AMPK 通路抑制剂 Compound C 则可消除沙格列汀促进成骨分化的作用。综上，沙格列汀通过激活 AMPKα/RUNX-2 增强了 MC3T3-E1 细胞的成骨分化能力。
