title: Effect of prolyl hydroxylase inhibitor-loaded collagen barrier membranes on osteoclastogenesis and osteoblastogenesis.
abstract: Prolyl hydroxylase inhibitors induce a proangiogenic response and are therefore proposed to optimize regenerative approaches in periodontics and oral surgery. Here the effect of the prolyl hydroxylase inhibitors dimethyloxalylglycine and deferoxamine, released from collagen barrier membranes, on osteoclastogenesis and osteoblastogenesis was evaluated. Collagen barrier membranes were loaded with dimethyloxalylglycine and deferoxamine. Release studies were performed and supernatants were taken after 1, 3, 6, 24, and 48 h. The effect of these supernatants on osteoblast- and osteoclast-precursor cells was evaluated. Furthermore, dose response studies for dimethyloxalylglycine and deferoxamine were performed. Osteoclastogenesis was evaluated with RAW 264.7 cells based on the number of multinuclear tartrate-resistant acid phosphatase positive cells. Osteoblastogenesis was evaluated with MC3T3-E1 cells based on alkaline phosphatase. Metabolic activity and cell proliferation were assessed based on MTT and BrdU assays. Vascular endothelial growth factor production was evaluated using an immunoassay. We found that supernatants taken in the first hour from collagen barrier membranes loaded with dimethyloxalylglycine or deferoxamine reduced osteoclastogenesis. Osteoblastogenesis was not reduced significantly. Cell proliferation and metabolic activity of RAW 264.7 and MC3T3-E1 cells were inhibited by supernatants of collagen barrier membranes loaded with deferoxamine but not dimethyloxalylglycine. In RAW 264.7 cell culture, vascular endothelial growth factor production was increased only by supernatants of collagen barrier membranes loaded with dimethyloxalylglycine, but not deferoxamine. In MC3T3-E1 cell culture, supernatants of collagen barrier membranes loaded with dimethyloxalylglycine and deferoxamine both increased vascular endothelial growth factor production. Direct measurements showed that the majority of dimethyloxalylglycine and deferoxamine is released in the first hours. Dose-response studies supported the divergent effects of deferoxamine and dimethyloxalylglycine in RAW 264.7 and MC3T3-E1 cultures. Our findings show diverse effects of dimethyloxalylglycine- and deferoxamine-loaded collagen barrier membranes during osteoclastogenesis and osteoblastogenesis. Preclinical studies will reveal if the increase in vascular endothelial growth factor together with the inhibitory effect on osteoclasts can stimulate oral tissue regeneration.
authors.affiliation: 1 Department of Oral Surgery, School of Dentistry, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Edelmayer
authors.affiliation: 2 Department of Conservative Dentistry and Periodontology, School of Dentistry, Medical University of Vienna, Vienna, Austria.
authors.forename: Diana
authors.initials: D
authors.lastname: Al-Habbal
authors.affiliation: 1 Department of Oral Surgery, School of Dentistry, Medical University of Vienna, Vienna, Austria.|2 Department of Conservative Dentistry and Periodontology, School of Dentistry, Medical University of Vienna, Vienna, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pensch
authors.affiliation: 2 Department of Conservative Dentistry and Periodontology, School of Dentistry, Medical University of Vienna, Vienna, Austria.
authors.forename: Klara
authors.initials: K
authors.lastname: Janjić
authors.affiliation: 2 Department of Conservative Dentistry and Periodontology, School of Dentistry, Medical University of Vienna, Vienna, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Agis
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000600:Amino Acids, Dicarboxylic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D001862:Bone Resorption / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D003094:Collagen / Q000737:chemistry*; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology*; D048091:Guided Tissue Regeneration; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis; D010539:Permeability; D064800:Prolyl-Hydroxylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D023822:Tissue Engineering; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D064800:Prolyl-Hydroxylase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D000469:Alkaline Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D003676:Deferoxamine; C040947:oxalylglycine
keywords: Hypoxia mimetic agents; collagen barrier membranes; guided bone regeneration; hypoxia inducible factor-1; tissue engineering