title: Compression induces Ephrin-A2 in PDL fibroblasts via c-fos.
abstract: Ephrin-A2-EphA2 and ephrin-B2-EphB4 interactions have been implicated in the regulation of bone remodeling. We previously demonstrated a potential role for members of the Eph-ephrin family of receptor tyrosine kinases for bone remodeling during orthodontic tooth movement: compression-dependent upregulation of ephrin-A2 in fibroblasts of the periodontal ligament (PDL) attenuated osteogenesis in osteoblasts of the alveolar bone. However, factors affecting the regulation of ephrin-A2 expression upon the application of compressive forces remained unclear. Here, we report a mechano-dependent pathway of ephrin-A2 induction in PDL fibroblasts (PDLFs) involving extracellular signal-regulated kinases (ERK) 1/2 and c-fos. PDLF subjected to compressive forces (30.3 g/cm(2)) upregulated c-fos and ephrin-A2 mRNA and protein expression and displayed increased ERK1/2 phosphorylation. Inhibition of the MAP kinase kinase (MEK)/ERK1/2 pathway using the specific MEK inhibitor U0126 significantly reduced ephrin-A2 messenger RNA upregulation upon compression. Silencing of c-fos using a small interfering RNA approach led to a significant inhibition of ephrin-A2 induction upon the application of compressive forces. Interestingly, ephrin-A2 stimulation of PDLF induced c-fos expression and led also to the induction of ephrin-A2 expression. Using a reporter gene construct in murine 3T3 cells, we found that ephrin-A2 was able to stimulate serum response element (SRE)-dependent luciferase activity. As the regulation of c-fos is SRE dependent, ephrin-A2 might induce c-fos via SRE activation. Taken together, we provide evidence for an ERK1/2- and c-fos-dependent regulation of ephrin-A2 in compressed PDLF and suggest a novel pathway for ephrin-A2 induction emanating from ephrin-A2 itself. We showed previously that ephrin-A2 at compression sites might contribute to tooth movement by inhibiting osteogenic differentiation. The regulatory pathway of ephrin-A2 induction during tooth movement identified in this study might be accessible for pharmacological interventions.
authors.affiliation: Department of Orthodontics and Dentofacial Orthopaedics, Dental School, University of Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sen
authors.affiliation: Department of Orthodontics and Dentofacial Orthopaedics, Dental School, University of Heidelberg, Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Diercke
authors.affiliation: Department of Orthodontics and Dentofacial Orthopaedics, Dental School, University of Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zingler
authors.affiliation: Department of Orthodontics and Dentofacial Orthopaedics, Dental School, University of Heidelberg, Heidelberg, Germany.
authors.forename: C J
authors.initials: CJ
authors.lastname: Lux
authors.affiliation: Department of Orthodontics and Dentofacial Orthopaedics, Dental School, University of Heidelberg, Heidelberg, Germany ralf.erber@med.uni-heidelberg.de.
authors.forename: R
authors.initials: R
authors.lastname: Erber
mesh_terms: D016475:3T3 Cells; D000293:Adolescent; D000818:Animals; D001696:Biomechanical Phenomena; D002070:Butadienes / Q000494:pharmacology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002648:Child; D036383:Ephrin-A2 / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D010513:Periodontal Ligament / Q000166:cytology*; D011312:Pressure; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage; D027602:Serum Response Element / Q000502:physiology; D013314:Stress, Mechanical; D015533:Transcriptional Activation; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D002070:Butadienes; D036383:Ephrin-A2; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; C113580:U 0126; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Eph family receptors; cellular mechanotransduction; mitogen-activated protein kinase 1; periodontal ligament; serum response element; tooth movement