title: The transmembrane transport of metformin by osteoblasts from rat mandible.
abstract: Previous studies have demonstrated that metformin, one of systemic antihyperglycemic drugs, can slow bone loss caused by diabetes mellitus and has an osteogenic action on osteoblasts in vitro. It is tempting to speculate that metformin would be transported into bone tissues around dental implant by topical administration to improve the bone-implant contact in diabetic patients. In this study, the osteoblasts from rat mandible were cultured with 5.5 mM (control) or 16.5 mM d-glucose, then the uptake of metformin by osteoblasts was detected with high performance liquid chromatography (HPLC). Rat organic cation transporter (rOct) expression was characterized by immunocytochemistry, RT-PCR and Western blotting. It was found that, the uptake of metformin was saturable, Na(+)-dependent, affected by extracellular pH and inhibited by both phenformin and cimetidine (an inhibitor of Octs). rOct1 but no rOct2 was expressed extensively in osteoblasts and the protein level of rOct1 could be up-regulated by metformin. The uptake of metformin and phosphorylated-rOct1 at hyperglycaemic cell culture (16.5 mM d-glucose) significantly increased versus 5.5 mM control (p < 0.05). In conclusion, rat osteoblasts have the ability to transport the metformin intra-cellularly, the uptake of metformin by osteoblasts is a secondary active transportation mediated by rOct1 and high-glucose can improve the uptake of metformin by osteoblasts through phosphorylation of rOct1. The current results suggest that metformin could be used for dental implant topically in type 2 diabetic patients to increase the bone formation, therefore, to enhance the success rate of dental implants clinically.
authors.affiliation: Department of Stomatology, China PLA General Hospital, Beijing 100853, China.
authors.forename: Long
authors.initials: L
authors.lastname: Ma
authors.forename: Xia
authors.initials: X
authors.lastname: Wu
authors.forename: E
authors.initials: E
authors.lastname: Ling-Ling
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Wang
authors.forename: Hong-Chen
authors.initials: HC
authors.lastname: Liu
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology*; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000032:analysis / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D008334:Mandible / Q000166:cytology; D008687:Metformin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D050482:Catecholamine Plasma Membrane Transport Proteins; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; C493212:Slc22a1 protein, rat; D008687:Metformin; D005947:Glucose