School of Medicine, Shandong University , Ji'nan , China.
Department of Orthopedics, Qilu Hospital, Shandong University , Ji'nan , China.
Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):3569-3576. doi: 10.1080/21691401.2019.1649270.
Osteoporosis-related bone fracture and falls have a severe impact on patients' daily lives. Osteoblasts are bone-building cells that play a vital role in bone formation and remodeling. Imbalanced osteoblast differentiation could lead to osteoporosis. GPR39 is an orphan G protein-coupled receptor that mediates metabolic pathways. In this study, we show that GPR39 is expressed in MC3T3-E1 cells. Osteoblast differentiation culture media induces GPR39, suggesting that GPR39 is a differentiation-responsive factor. Activation of GPR39 using its selective agonist TC-G 1008 induces alkaline phosphatase (ALP), osteocalcin (OCN), and type I collagen (Col-I) expression, and increases cellular ALP activity and calcium deposition, implying that GPR activation promotes cells toward osteoblast differentiation. Treatment with TC-G 1008 also increases Runx-2 expression and AMPK activation. However, the inhibition of AMPK by Compound C abolished TC-G 1008-mediated ALP, OCN, and Col-I induction, and reduces ALP activity and cellular calcium deposition as well as Runx-2 induction. These data indicate that TC-G 1008-mediated GPR39 activation involves AMPK-mediated Runx-2 induction. In summary, our study uncovers a new role of GPR39 activation in osteoblast differentiation, implying that GPR39 could be a promising therapeutic target for osteoporosis.
骨质疏松症相关的骨折和跌倒对患者的日常生活造成严重影响。成骨细胞是构建骨骼的细胞，在骨形成和重塑中起着至关重要的作用。成骨细胞分化失衡可导致骨质疏松症。GPR39 是一种孤儿 G 蛋白偶联受体，介导代谢途径。在本研究中，我们表明 GPR39 在 MC3T3-E1 细胞中表达。成骨细胞分化培养基诱导 GPR39 的表达，表明 GPR39 是一种分化反应性因子。使用其选择性激动剂 TC-G 1008 激活 GPR39 可诱导碱性磷酸酶 (ALP)、骨钙素 (OCN) 和 I 型胶原 (Col-I) 的表达，并增加细胞 ALP 活性和钙沉积，表明 GPR 激活可促进细胞向成骨细胞分化。TC-G 1008 处理还增加了 Runx-2 的表达和 AMPK 的激活。然而，化合物 C 抑制 AMPK 可消除 TC-G 1008 介导的 ALP、OCN 和 Col-I 的诱导，并降低 ALP 活性和细胞钙沉积以及 Runx-2 的诱导。这些数据表明，TC-G 1008 介导的 GPR39 激活涉及 AMPK 介导的 Runx-2 诱导。总之，我们的研究揭示了 GPR39 激活在成骨细胞分化中的新作用，表明 GPR39 可能成为骨质疏松症的有希望的治疗靶点。
