Nagano Akihiro, Arioka Masaki, Takahashi-Yanaga Fumi, Matsuzaki Etsuko, Sasaguri Toshiyuki
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Periodontology Section, Division of Oral Rehabilitation, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan.
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Pharmacol Sci. 2017 Jan;133(1):18-24. doi: 10.1016/j.jphs.2016.11.003. Epub 2016 Dec 1.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to impair bone healing. We previously reported that in colon cancer cells, celecoxib, a COX-2-selective NSAID, inhibited the canonical Wnt/β-catenin signaling pathway. Since this pathway also plays an important role in osteoblast growth and differentiation, we examined the effect of celecoxib on maturation of osteoblast-like cell line MC3T3-E1. Celecoxib induced degradation of transcription factor 7-like 2, a key transcription factor of the canonical Wnt pathway. Subsequently, we analyzed the effect of celecoxib on two osteoblast differentiation markers; runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP), both of which are the products of the canonical Wnt pathway target genes. Celecoxib inhibited the expression of both RUNX2 and ALP by suppressing their promoter activity. Consistent with these observations, celecoxib also strongly inhibited osteoblast-mediated mineralization. These results suggest that celecoxib inhibits osteoblast maturation by suppressing Wnt target genes, and this could be the mechanism that NSAIDs inhibit bone formation and fracture healing.
非甾体抗炎药（NSAIDs）已被证明会损害骨愈合。我们之前报道过，在结肠癌细胞中，COX-2选择性NSAID塞来昔布抑制了经典的Wnt/β-连环蛋白信号通路。由于该通路在成骨细胞的生长和分化中也起着重要作用，我们研究了塞来昔布对成骨样细胞系MC3T3-E1成熟的影响。塞来昔布诱导了经典Wnt通路的关键转录因子7样2的降解。随后，我们分析了塞来昔布对两种成骨细胞分化标志物的影响；即与 runt 相关的转录因子2（RUNX2）和碱性磷酸酶（ALP），这两者都是经典Wnt通路靶基因的产物。塞来昔布通过抑制其启动子活性来抑制RUNX2和ALP的表达。与这些观察结果一致，塞来昔布也强烈抑制成骨细胞介导的矿化。这些结果表明，塞来昔布通过抑制Wnt靶基因来抑制成骨细胞成熟，这可能是NSAIDs抑制骨形成和骨折愈合的机制。
