Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Orthopedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
FASEB J. 2019 Sep;33(9):9828-9841. doi: 10.1096/fj.201802242RR. Epub 2019 Jul 10.
Identification of anti-osteoclastogenic agents is important for the treatment of bone loss diseases that feature excessive osteoclast (OC) activity and bone resorption. Tranylcypromine (TCP), an irreversible inhibitor of monoamine oxidase (MAO), has been used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders. TCP has been discovered to exert anabolic effect on osteoblasts, and MAO-A has also been verified as an important mediator in prostate cancer cells to accelerate osteoclastogenesis. In current study, we were focused on TCP and MAO-A effects on osteoclastogenesis. As illustrated by tartrate-resistant acid phosphatase staining, TCP was capable of inhibiting osteoclastogenesis induced by receptor activators of the NF-κB ligand (RANKL) in bone marrow-derived macrophage cells without any cytotoxicity. It was also shown to effectively suppress bone resorption of OCs. The subsequent study revealed that TCP inhibited osteoclastogenesis-related genes in a time-dependent manner through protein kinase B (AKT)-mediated mechanism followed by the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-c-fos pathway. And TCP could overcome the osteoclastogenic effects of AKT activator SC79. In addition, our results indicated that the expression and catalytic activity of MAO-A were up-regulated by RANKL stimulation and down-regulated by TCP and . Furthermore, the effects of MAO-A knockdown on OC differentiation indicated that MAO-A played an important role in osteoclastogenesis and might contribute to the inhibitory effects of TCP. And AKT, NFATc1, and c-fos were involved in the MAO-A pathway. Notably, our study reflected that TCPs were capable of restoring the bone loss in LPS-induced calvaria osteolysis and estrogen deficiency-induced osteoporosis models. Thus, our current work provided a potential option for the treatment of bone loss diseases and highlighted the important role of MAO-A in osteoclastogenesis as well.-Liu, Z., Yang, K., Yan, X., Wang, T., Jiang, T., Zhou, Q., Qi, J., Qian, N., Zhou, H., Chen, B., Huang, P., Guo, L., Zhang, X., Xu, X., Jiang, M., Deng, L. The effects of tranylcypromine on osteoclastogenesis and .
鉴定抗破骨细胞生成剂对于治疗破骨细胞（OC）活性和骨吸收过度的骨丢失疾病非常重要。反苯环丙胺（TCP）是一种不可逆的单胺氧化酶（MAO）抑制剂，已在临床治疗情绪和焦虑障碍中用作抗抑郁药和抗焦虑药。已发现 TCP 对成骨细胞具有合成代谢作用，并且 MAO-A 也已被验证为前列腺癌细胞中加速破骨细胞生成的重要介质。在当前的研究中，我们专注于 TCP 和 MAO-A 对破骨细胞生成的影响。如抗酒石酸酸性磷酸酶染色所示，TCP 能够抑制骨髓来源的巨噬细胞中核因子κB 配体（RANKL）诱导的破骨细胞生成，而没有任何细胞毒性。它还能够有效抑制 OC 的骨吸收。随后的研究表明，TCP 通过蛋白激酶 B（AKT）介导的机制，随后是活化 T 细胞核因子，细胞质 1（NFATc1）-c-fos 途径，以时间依赖性方式抑制破骨细胞生成相关基因。并且 TCP 可以克服 AKT 激活剂 SC79 的破骨细胞生成作用。此外，我们的结果表明，MAO-A 的表达和催化活性通过 RANKL 刺激而上调，并通过 TCP 和 下调。此外，MAO-A 敲低对 OC 分化的影响表明，MAO-A 在破骨细胞生成中起重要作用，并且可能有助于 TCP 的抑制作用。AKT、NFATc1 和 c-fos 参与了 MAO-A 通路。值得注意的是，我们的 研究表明，TCP 能够恢复 LPS 诱导的颅骨骨溶解和雌激素缺乏诱导的骨质疏松模型中的骨丢失。因此，我们目前的工作为治疗骨丢失疾病提供了一种潜在的选择，并强调了 MAO-A 在破骨细胞生成中的重要作用。
