title: MicroRNA-138 Inhibits Periodontal Progenitor Differentiation under Inflammatory Conditions.
abstract: Inflammatory conditions as they occur during periodontal disease often result in decreased alveolar bone levels and a loss of connective tissue homeostasis. Here we have focused on the effect of microRNA-138 (miR-138) as a potential regulator of periodontal stem cells as they affect homeostasis during inflammatory conditions. Our data indicate that miR-138 was significantly upregulated in our periodontal disease animal model. Interaction of miR-138 with a predicted targeting site on the osteocalcin (OC) promoter resulted in a 3.7-fold reduction of luciferase activity in promoter assays compared with controls; and miR-138 overexpression in periodontal progenitors significantly inhibited OC (3.4-fold), Runx2 (2.8-fold), and collagen I (2.6-fold). Moreover, treatment with inflammatory modulators such as interleukin (IL)-6 and lipopolysaccharide (LPS) resulted in a significant 2.2-fold (IL-6) or 1.9-fold (LPS) increase in miR-138 expression, while OC and Runx2 expression was significantly decreased as a result of treatment with each inflammatory mediator. Further defining the role of miR-138 in the OC-mediated control of mineralization, we demonstrated that the LPS-induced downregulation of OC expression was partially reversed after miR-138 knockdown. LPS, miR-138 mimic, and OC small interfering RNA inhibited osteoblast differentiation marker alkaline phosphatase activity, while miR-138 inhibitor and OC protein addition enhanced alkaline phosphatase activity. Supporting the role of OC as an essential modulator of osteoblast differentiation, knockdown of miR-138 or addition of OC protein partially rescued alkaline phosphatase activity in periodontal ligament (PDL) cells subjected to LPS treatment. Our data establish miR-138 inhibitor as a potential therapeutic agent for the prevention of the bone loss associated with advanced periodontal disease.
authors.affiliation: Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Luan
authors.affiliation: Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Francis
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gopinathan
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pediatric Dentistry, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Periodontics, Baylor College of Dentistry, Dallas, TX, USA diekwisch@bcd.tamhsc.edu.
authors.forename: T G H
authors.initials: TG
authors.lastname: Diekwisch
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000032:analysis; D050659:Core Binding Factor Alpha 1 Subunit / Q000032:analysis; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000032:analysis; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D015675:Osteocalcin / Q000032:analysis; D010513:Periodontal Ligament / Q000166:cytology*; D010518:Periodontitis / Q000382:microbiology / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*
chemical_list: D024042:Collagen Type I; D050659:Core Binding Factor Alpha 1 Subunit; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; C581260:MIRN138 microRNA, rat; D035683:MicroRNAs; D034741:RNA, Small Interfering; C493717:Runx2 protein, rat; D015675:Osteocalcin; D008156:Luciferases; D000469:Alkaline Phosphatase
keywords: alveolar bone loss; osteocalcin; osteogenesis; periodontal diseases; periodontal ligament; stem cells