Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
Biochem Pharmacol. 2013 Sep 15;86(6):782-90. doi: 10.1016/j.bcp.2013.07.015. Epub 2013 Aug 6.
Trapidil, a platelet-derived growth factor antagonist, was originally developed as a vasodilator and anti-platelet agent and has been used to treat patients with ischemic coronary heart, liver, and kidney disease. In this study, we investigated the effects of trapidil on osteoclastogenesis and elucidated the possible mechanism of action of trapidil. Trapidil strongly inhibited osteoclast formation in co-cultures of bone marrow cells and osteoblasts without affecting receptor activator of NF-κB ligand (RANKL) or osteoprotegerin expression in osteoblasts. In addition, trapidil suppressed RANKL-induced osteoclast formation from osteoclast precursors. Trapidil reduced RANKL-induced expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis, without affecting the expression of c-Fos that functions as a key upstream activator of NFATc1 during osteoclastogenesis. Ectopic expression of a constitutively active form of NFATc1 reversed the anti-osteoclastogenic effect of trapidil, indicating that NFATc1 is a critical target of the anti-osteoclastogenic action of trapidil. RANKL-induced calcium oscillation and Pim-1 expression, which are required for NFATc1 induction and osteoclastogenesis, were abrogated by trapidil. Consistent with the in vitro results, trapidil had a potent inhibitory effect on osteoclast formation and bone resorption induced by interleukin-1 in an animal model. Taken together, our data demonstrate that trapidil abrogates RANKL-induced calcium oscillation and Pim-1 expression required for NFATc1 induction, thereby inhibiting osteoclastogenesis.
曲匹地尔是一种血小板衍生生长因子拮抗剂，最初被开发为血管扩张剂和抗血小板药物，用于治疗缺血性冠心病、肝和肾病患者。在这项研究中，我们研究了曲匹地尔对破骨细胞生成的影响，并阐明了曲匹地尔作用的可能机制。曲匹地尔在骨髓细胞和成骨细胞的共培养物中强烈抑制破骨细胞形成，而不影响成骨细胞中核因子κB 受体激活配体（RANKL）或骨保护素的表达。此外，曲匹地尔抑制 RANKL 诱导的破骨细胞前体形成破骨细胞。曲匹地尔降低 RANKL 诱导的核因子活化 T 细胞胞浆 1（NFATc1）表达，NFATc1 是破骨细胞生成的主要转录因子，而不影响 c-Fos 的表达，c-Fos 在破骨细胞生成过程中作为 NFATc1 的关键上游激活剂。NFATc1 的组成性激活形式的异位表达逆转了曲匹地尔的抗破骨细胞生成作用，表明 NFATc1 是曲匹地尔抗破骨细胞生成作用的关键靶标。RANKL 诱导的钙振荡和 Pim-1 表达，这是 NFATc1 诱导和破骨细胞生成所必需的，被曲匹地尔阻断。与体外结果一致，曲匹地尔在动物模型中对白细胞介素-1 诱导的破骨细胞形成和骨吸收具有很强的抑制作用。总之，我们的数据表明，曲匹地尔阻断了 RANKL 诱导的 NFATc1 诱导所需的钙振荡和 Pim-1 表达，从而抑制了破骨细胞生成。
