Graduate School of Jinzhou Medical University, Jinzhou, China.
Department of Orthopedics, Changhai Hospital, Second Military Medical University, Shanghai, China.
Pharmacology. 2018;102(5-6):272-280. doi: 10.1159/000492576. Epub 2018 Sep 18.
The function of melatonin (MLT) in promoting fracture healing has been demonstrated in previous studies. However, the molecular mechanism underlying therapeutic effects of MLT is not entirely clear. In this study, mesenchymal stem cells (MSCs) were isolated from rat bone marrow and identified by flow cytometry. We found that MLT treatment upregulated the neuropeptide Y (NPY) and NPY receptor Y1 (NPY1R) expression, and promoted the proliferation and migration of MSCs, which was suppressed by BIBP3226, an inhibitor of NPY1R. Moreover, the levels of NPY and NPY1R in MSCs undergoing osteoblastic differentiation were upregulated after MLT administration. MLT-induced osteoblastic differentiation of MSCs was suppressed by BIBP3226 treatment, as evidenced by decreased levels of alkaline phosphatase (ALP), collagen type I α1 chain, osteocalcin, and runt-related transcription factor 2, downregulated activity of ALP, as well as reduced calcium nodule formation. Furthermore, we demonstrated that MLT could promote fracture healing in a rat model of femoral fracture, which was accompanied by the elevated expression of NPY and NPY1R. The administration of BIBP3226 inhibited fracture healing mediated by MLT. To sum up, our results show that MLT promotes osteoblastic differentiation of MSCs and fracture healing by NPY/NPY1R signaling.
褪黑素（MLT）在促进骨折愈合中的作用已在先前的研究中得到证实。然而，MLT 治疗效果的分子机制尚不完全清楚。在这项研究中，我们从大鼠骨髓中分离出间充质干细胞（MSCs），并通过流式细胞术进行鉴定。我们发现，MLT 处理上调了神经肽 Y（NPY）和 NPY 受体 Y1（NPY1R）的表达，并促进了 MSCs 的增殖和迁移，而 NPY1R 的抑制剂 BIBP3226 则抑制了这一过程。此外，在给予 MLT 后，MSC 向成骨细胞分化的 NPY 和 NPY1R 水平上调。BIBP3226 处理抑制了 MLT 诱导的 MSCs 成骨分化，表现为碱性磷酸酶（ALP）、Ⅰ型胶原α1 链、骨钙素和 runt 相关转录因子 2 水平降低，ALP 活性降低，以及钙结节形成减少。此外，我们证明 MLT 可以促进股骨骨折大鼠模型中的骨折愈合，同时伴随着 NPY 和 NPY1R 的表达上调。BIBP3226 的给药抑制了 MLT 介导的骨折愈合。总之，我们的结果表明，MLT 通过 NPY/NPY1R 信号促进 MSCs 的成骨分化和骨折愈合。
