title: Tension Force Downregulates Matrix Metalloproteinase Expression and Upregulates the Expression of Their Inhibitors through MAPK Signaling Pathways in MC3T3-E1 cells.
abstract: OBJECTIVE
  Matrix metalloproteinases (MMPs), produced by osteoblasts, catalyze the turnover of extracellular matrix (ECM) molecules in osteoid, and the regulation of MMP activity depends on interactions between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We focused on the degradation process of ECM in osteoid that was exposed to mechanical strain, and conducted an in vitro study using MC3T3-E1 osteoblastic cells to examine the effects of tension force (TF) on the expression of MMPs and TIMPs, and activation of mitogen-activated protein kinase (MAPK) pathways.
  
  
  METHODS
  Cells were incubated on flexible-bottomed culture plates and stimulated with or without cyclic TF for 24 hours. The expression of MMPs and TIMPs was examined at mRNA and protein levels by real-time RT-PCR and Western blotting, respectively. The phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK, and stress-activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) were examined by Western blotting.
  
  
  RESULTS
  TF decreased the expression of MMP-1, -3, -13 and phosphorylated ERK1/2. In contrast, TF increased the expression of TIMP-2, -3 and phosphorylated SAPK/JNK. The expression of MMP-2, -14, TIMP-1, -4 and phosphorylated p38 MAPK was unaffected by TF. MMP-1, -3 and -13 expression decreased in cells treated with the ERK inhibitor PD98059 compared with untreated control cells. The JNK inhibitor SP600125 inhibited the TF-induced upregulation of TIMP-2 and -3.
  
  
  CONCLUSIONS
  The results suggest that TF suppresses the degradation process that occurs during ECM turnover in osteoid via decreased production of MMP-1, -3 and -13, and increased production of TIMP-2 and -3 through the MAPK signaling pathways in osteoblasts.
authors.affiliation: 1. Nihon University Graduate School of Dentistry, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Karasawa
authors.affiliation: 2. Department of Oral Health Sciences, Nihon University School of Dentistry, Tokyo, Japan ; 3. Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: 2. Department of Oral Health Sciences, Nihon University School of Dentistry, Tokyo, Japan ; 3. Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nakai
authors.affiliation: 3. Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan ; 4. Department of Biochemistry, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tanabe
authors.affiliation: 2. Department of Oral Health Sciences, Nihon University School of Dentistry, Tokyo, Japan ; 3. Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kawato
authors.affiliation: 2. Department of Oral Health Sciences, Nihon University School of Dentistry, Tokyo, Japan ; 3. Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Maeno
authors.affiliation: 5. Department of Orthodontics, Nihon University School of Dentistry, Tokyo, Japan ; 6. Division of Clinical Research, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D010766:Phosphorylation; D013314:Stress, Mechanical; D015854:Up-Regulation
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases
keywords: matrix metalloproteinases; mechanical strain; mitogen-activated protein kinase; osteoblast; tissue inhibitors of metalloproteinases