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    • Pitolisant hydrochloride The drug repositioning strategy in

    2018-10-30

    The drug repositioning strategy, in which a drug currently used for a specific disease is applied to another disease, has gained increasing attention from both academia and industry in recent years (Abbott, 2002; Rothstein et al., 2005; Bian et al., 2009; Yamamoto et al., 2013; Matsushita et al., 2013; Takamatsu et al., 2014). The advantage of this strategy is that the identified drugs can be readily applied to clinical practice, because the optimal doses, adverse effects, and contraindications are already established. In this study, we identified by the drug repositioning strategy that lansoprazole, a proton pump inhibitor (PPI), upregulates Runx2 and induces osteoblastogenesis. We also proved the effect of lansoprazole in a rat model of femoral fracture in order to explore the possibilities of clinical application. We dissected the effect of lansoprazole and found that lansoprazole induces TRAF6 polyubiquitination, which then activates the noncanonical TAK1–p38 MAPK pathway and upregulates Runx2. Furthermore, in silico analysis predicted and site-directed mutagenesis revealed the binding of lansoprazole to a CYLD pocket and the inhibition of its deubiquitination activity by lansoprazole, which leads to enhanced polyubiquitination of TRAF6.
    Materials and Methods
    Results
    Discussion Our drug repositioning study revealed that lansoprazole, a proton pump inhibitor, has bone anabolic activity through upregulation of Runx2 and serves as an enhancer of BMP signaling. Using the drug repositioning strategy, Mundy and colleagues identified that statins that are commonly prescribed for hyperlipidemia enhance the BMP2 promoter activity (Mundy et al., 1999). Similar to lansoprazole, statins stimulate bone formation in animal models (Gutierrez et al., 2008). However, statins may (Edwards et al., 2000) or may not (Esposito et al., 2013) increase bone mineral density and prevent osteoporotic fractures in postmenopausal women. BMP-2 is a potent osteoinductive agent that is required for the initiation of fracture healing (Tsuji et al., 2006) and for the development and maturation of osteoblasts (Chen et al., 2012a). BMP-2, however, is also capable of inducing pluripotent mesenchymal Pitolisant hydrochloride into multiple lineages such as osteoblasts, chondrocytes, and adipocytes (Date et al., 2004). Controversial effects on bone metabolism of statins may be attributed to the diverse effects of BMP-2. On the contrary, Runx2 exclusively induces osteochondroblastogenesis (Komori, 2010), but Runx2 alone is not sufficient to induce the maturation of osteoblasts (Lee et al., 2000). Runx2 is upregulated by BMPs (Phimphilai et al., 2006), and the two molecules orchestrate to induce the development and maturation of osteoblasts (Leboy, 2006). Upregulation of BMPs by statins and upregulation of Runx2 by lansoprazole are expected to coordinately accelerate osteoblastogenesis, but further studies are required. BMP ligands bind to BMPRII, and facilitates the formation of a heterotetrameric receptor complex comprised of BMPRI and BMRPII, which then activates the canonical pathway through phosphorylation of the receptor-regulated Smads as well as the noncanonical MAPK pathways (Katagiri and Tsukamoto, 2013). For Runx2 activation, both canonical and noncanonical pathways play essential roles in mesenchymal precursor cells (Lee et al., 2002). Among the noncanonical pathways, activation of the TAK1–p38 MAPK axis is essential for Runx2 activation in mesenchymal precursor cells (Greenblatt et al., 2010). BMP-mediated formation of a BMPRI-II complex additionally induces accumulation of TRAF6 on the complex. TRAF6 is a ubiquitin ligase as well as a substrate polyubiquitinated by itself. The accumulation of TRAF6 enhances the synthesis of Lys63-linked autopolyubiquitin chains. The polyubiquitin chains confer a scaffold for the TAB-mediated adjacent placement of two TAK1 molecules, which leads to autophosphorylation of TAK1 (Xia et al., 2009; Landstrom, 2010; Sorrentino et al., 2008). The phosphorylated TAK1 then phosphorylates p38 MAPK. The activated p38 MAPK also activates other transcriptional factors that are essential for bone formation including Osterix and distal-less homeobox 5 (Dlx5) (Ulsamer et al., 2008; Ortuno et al., 2010). Dissection of underlying molecular mechanisms of the effect of lansoprazole revealed that lansoprazole has little or no effects on the canonical pathway, but activates the noncanonical TRAF6–TAK1–p38 MAPK pathway.