title: Mechano-transduction in periodontal ligament cells identifies activated states of MAP-kinases p42/44 and p38-stress kinase as a mechanism for MMP-13 expression.
abstract: BACKGROUND
  Mechano-transduction in periodontal ligament (PDL) cells is crucial for physiological and orthodontic tooth movement-associated periodontal remodelling. On the mechanistic level, molecules involved in this mechano-transduction process in PDL cells are not yet completely elucidated.
  
  
  RESULTS
  In the present study we show by western blot (WB) analysis and/or indirect immunofluorescence (IIF) that mechanical strain modulates the amount of the matrix metalloproteinase MMP-13, and induces non-coherent modulation in the amount and activity of signal transducing molecules, such as FAK, MAP-kinases p42/44, and p38 stress kinase, suggesting their mechanistic role in mechano-transduction. Increase in the amount of FAK occurs concomitant with increased levels of the focal contact integrin subunits beta3 and beta1, as indicated by WB or optionally by IIF. By employing specific inhibitors, we further identified p42/44 and p38 in their activated, i.e. phosphorylated state responsible for the expression of MMP-13. This finding may point to the obedience in the expression of this MMP as extracellular matrix (ECM) remodelling executioner from the activation state of mechano-transducing molecules. mRNA analysis by pathway-specific RT-profiler arrays revealed up- and/or down-regulation of genes assigning to MAP-kinase signalling and cell cycle, ECM and integrins and growth factors. Up-regulated genes include for example focal contact integrin subunit alpha3, MMP-12, MAP-kinases and associated kinases, and the transcription factor c-fos, the latter as constituent of the AP1-complex addressing the MMP-13 promotor. Among others, genes down-regulated are those of COL-1 and COL-14, suggesting that strain-dependent mechano-transduction may transiently perturbate ECM homeostasis.
  
  
  CONCLUSIONS
  Strain-dependent mechano-/signal-transduction in PDL cells involves abundance and activity of FAK, MAP-kinases p42/44, and p38 stress kinase in conjunction with the amount of MMP-13, and integrin subunits beta1 and beta3. Identifying the activated state of p42/44 and p38 as critical for MMP-13 expression may indicate the mechanistic contribution of mechano-transducing molecules on executioners of ECM homeostasis.
authors.affiliation: Department of Oral Biotechnology, Dental School, University of Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany.
authors.forename: Nelli
authors.initials: N
authors.lastname: Ziegler
authors.forename: Angel
authors.initials: A
authors.lastname: Alonso
authors.forename: Thorsten
authors.initials: T
authors.lastname: Steinberg
authors.forename: Dale
authors.initials: D
authors.lastname: Woodnutt
authors.forename: Annette
authors.initials: A
authors.lastname: Kohl
authors.forename: Eva
authors.initials: E
authors.lastname: Müssig
authors.forename: Simon
authors.initials: S
authors.lastname: Schulz
authors.forename: Pascal
authors.initials: P
authors.lastname: Tomakidi
mesh_terms: D000293:Adolescent; D002648:Child; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010513:Periodontal Ligament / Q000166:cytology / Q000201:enzymology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D039661:Integrin beta3; D012333:RNA, Messenger; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13