Matsuyama Atsushi, Higashi Sen, Tanizaki Saori, Morotomi Takahiko, Washio Ayako, Ohsumi Tomoko, Kitamura Chiaki, Takeuchi Hiroshi
Division of Endodontics and Restorative Dentistry, Department of Oral Functions, Kyushu Dental University, Kitakyushu, Japan.
Division of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Japan.
Clin Exp Pharmacol Physiol. 2018 Jan;45(1):75-83. doi: 10.1111/1440-1681.12846. Epub 2017 Sep 20.
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects primarily by inhibiting the activity of cyclooxygenase (COX), thus suppressing prostaglandin synthesis. Some NSAIDs are known to perform functions other than pain control, such as suppressing tumour cell growth, independent of their COX-inhibiting activity. To identify NSAIDs with COX-independent activity, we examined various NSAIDs for their ability to inhibit osteoblastic differentiation using the mouse pre-osteoblast cell line MC3T3-E1. Only celecoxib and valdecoxib strongly inhibited osteoblastic differentiation, and this effect was not correlated with COX-inhibiting activity. Moreover, 2,5-dimethyl (DM)-celecoxib, a celecoxib analogue that does not inhibit COX activity, also inhibited osteoblastic differentiation. Celecoxib and DM-celecoxib inhibited osteoblastic differentiation induced by bone morphogenetic protein (BMP)-2 in C2C12 mouse myoblast cell line. Although celecoxib suppresses the growth of some tumour cells, the viability and proliferation of MC3T3-E1 cells were not affected by celecoxib or DM-celecoxib. Instead, celecoxib and DM-celecoxib suppressed BMP-2-induced phosphorylation of Smad1/5, a major downstream target of BMP receptor. Although it is well known that COX plays important roles in osteoblastic differentiation, these results suggest that some NSAIDs, such as celecoxib, have targets other than COX and regulate phospho-dependent intracellular signalling, thereby modifying bone remodelling.
非甾体抗炎药（NSAIDs）主要通过抑制环氧化酶（COX）的活性发挥作用，从而抑制前列腺素的合成。已知一些NSAIDs除了具有止痛作用外，还具有其他功能，例如抑制肿瘤细胞生长，这与其COX抑制活性无关。为了鉴定具有不依赖COX活性的NSAIDs，我们使用小鼠前成骨细胞系MC3T3-E1检测了各种NSAIDs抑制成骨细胞分化的能力。只有塞来昔布和伐地昔布强烈抑制成骨细胞分化，且这种作用与COX抑制活性无关。此外，2,5-二甲基（DM）-塞来昔布，一种不抑制COX活性的塞来昔布类似物，也抑制成骨细胞分化。塞来昔布和DM-塞来昔布抑制了C2C12小鼠成肌细胞系中骨形态发生蛋白（BMP）-2诱导的成骨细胞分化。虽然塞来昔布抑制某些肿瘤细胞的生长，但MC3T3-E1细胞的活力和增殖不受塞来昔布或DM-塞来昔布的影响。相反，塞来昔布和DM-塞来昔布抑制了BMP-2诱导的Smad1/5磷酸化，Smad1/5是BMP受体的主要下游靶点。虽然众所周知COX在成骨细胞分化中起重要作用，但这些结果表明，一些NSAIDs，如塞来昔布，除了COX外还有其他靶点，并调节磷酸依赖性细胞内信号传导，从而改变骨重塑。
