Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Department of Internal Medicine,The General Hospital of Jinshui District, Zhengzhou, 450052, China.
Biomed Pharmacother. 2020 Sep;129:109796. doi: 10.1016/j.biopha.2019.109796. Epub 2020 Jun 16.
Osteoporosis is a common debilitating bone disease characterized by loss of bone mass and degradation of the bone architecture, which is primarily driven by dysregulated differentiation of mesenchymal stem cells into bone-producing osteoblasts. Osteoblasts contribute to bone formation by secreting various proteins that guide the deposition of bone extracellular matrix, such as alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). The Wnt/β-catenin pathway is widely recognized as a regulator of bone mass and is required to maintain bone homeostasis. Hormones have long been recognized as playing a key role in bone metabolism, and in recent years, growing evidence has shown that diabetes is a risk factor for osteoporosis. In the present study, we investigated the effects of the antidiabetic drug anagliptin on the differentiation and mineralization of osteoblasts induced by osteogenic medium. Anagliptin promotes insulin production via inhibition of dipeptidyl peptidase IV (DPP-4), an enzyme that targets the incretin hormone glucagon-like peptide 1 (GLP-1) for degradation. Our findings show that anagliptin significantly increases the differentiation of MSCs into osteoblasts via activation of RUNX2. Anagliptin significantly increased matrix deposition and mineralization by osteoblasts, as evidenced by elevated levels of ALP, OCN, OPN, and BMP-2. We further demonstrate that anagliptin activates the canonical and noncannonical Wnt signaling pathways and that silencing of Wnt/β-catenin signaling completely abolished the effects of anagliptin. Thus, anagliptin might be a safe, effective therapy for type II diabetes that might show promise as a therapy against osteoporosis.
骨质疏松症是一种常见的骨骼疾病，其特征是骨量减少和骨骼结构退化，主要是由间充质干细胞向产生骨的成骨细胞分化失调引起的。成骨细胞通过分泌各种指导骨细胞外基质沉积的蛋白质来促进骨形成，如碱性磷酸酶（ALP）、骨钙素（OCN）和骨桥蛋白（OPN）。Wnt/β-catenin 通路被广泛认为是骨量的调节剂，对于维持骨稳态是必需的。激素一直被认为在骨骼代谢中起着关键作用，近年来，越来越多的证据表明糖尿病是骨质疏松症的一个风险因素。在本研究中，我们研究了抗糖尿病药物 anagliptin 对成骨培养基诱导的成骨细胞分化和矿化的影响。Anagliptin 通过抑制二肽基肽酶 4（DPP-4）来促进胰岛素的产生，DPP-4 是一种针对肠降血糖素激素胰高血糖素样肽 1（GLP-1）进行降解的酶。我们的研究结果表明，anagliptin 通过激活 RUNX2 显著促进 MSC 向成骨细胞分化。Anagliptin 显著增加了成骨细胞基质的沉积和矿化，这表现为碱性磷酸酶（ALP）、骨钙素（OCN）、骨桥蛋白（OPN）和骨形态发生蛋白 2（BMP-2）水平的升高。我们进一步证明，anagliptin 激活了经典和非经典的 Wnt 信号通路，并且 Wnt/β-catenin 信号通路的沉默完全消除了 anagliptin 的作用。因此，anagliptin 可能是一种安全有效的治疗 2 型糖尿病的药物，并且可能有希望作为治疗骨质疏松症的方法。
