title: Rebamipide delivered by brushite cement enhances osteoblast and macrophage proliferation.
abstract: Many of the bioactive agents capable of stimulating osseous regeneration, such as bone morphogenetic protein-2 (BMP-2) or prostaglandin E2 (PGE2), are limited by rapid degradation, a short bioactive half-life at the target site in vivo, or are prohibitively expensive to obtain in large quantities. Rebamipide, an amino acid modified hydroxylquinoline, can alter the expression of key mediators of bone anabolism, cyclo-oxygenase 2 (COX-2), BMP-2 and vascular endothelial growth factor (VEGF), in diverse cell types such as mucosal and endothelial cells or chondrocytes. The present study investigates whether Rebamipide enhances proliferation and differentiation of osteoblasts when delivered from brushite cement. The reactive oxygen species (ROS) quenching ability of Rebampide was tested in macrophages as a measure of bioactivity following drug release incubation times, up to 14 days. Rebamipide release from brushite occurs via non-fickian diffusion, with a rapid linear release of 9.70% ± 0.37% of drug per day for the first 5 days, and an average of 0.5%-1% per day thereafter for 30 days. Rebamipide slows the initial and final cement setting time by up to 3 and 1 minute, respectively, but does not significantly reduce the mechanical strength below 4% (weight percentage). Pre-osteoblast proliferation increases by 24% upon exposure to 0.4 uM Rebamipide, and by up to 73% when Rebamipide is delivered via brushite cement. Low doses of Rebamipide do not adversely affect peak alkaline phosphatase activity in differentiating pre-osteoblasts. Rebamipide weakly stimulates proliferation in macrophages at low concentrations (118 ± 7.4% at 1 uM), and quenches ROS by 40-60%. This is the first investigation of Rebamipide in osteoblasts.
authors.affiliation: Division of Applied Material Science, Department of Engineering Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Pujari-Palmer
authors.affiliation: Division of Applied Material Science, Department of Engineering Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Shiuli
authors.initials: S
authors.lastname: Pujari-Palmer
authors.affiliation: Division of Applied Material Science, Department of Engineering Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Engqvist
authors.affiliation: Division of Applied Material Science, Department of Engineering Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Marjam
authors.initials: M
authors.lastname: Karlsson Ott
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001843:Bone Cements / Q000493:pharmacokinetics / Q000494:pharmacology*; D002130:Calcium Phosphates / Q000493:pharmacokinetics / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001843:Bone Cements; D002130:Calcium Phosphates; D003692:Delayed-Action Preparations; D015363:Quinolones; C052785:rebamipide; C494366:calcium phosphate, dibasic, dihydrate; D000409:Alanine