title: Induction of MMP-13 expression in bone-metastasizing cancer cells by type I collagen through integrin α1β1 and α2β1-p38 MAPK signaling.
abstract: BACKGROUND
  Breast cancer cells frequently metastasize to the skeleton and produce and secrete proteinases, such as matrix metalloproteinase-13 (MMP-13), which promote destruction of the bone matrix. However, the mechanism of MMP-13 expression induced in areas of bone metastasis is unknown. Here, the interaction between tumors and type I collagen in bone metastasis was investigated.
  
  
  METHODS
  A mouse model of bone metastasis was prepared by inoculating mice with suspensions of cells of the human metastatic breast cancer cell line MDA-MB-231 via the left cardiac ventricle. MMP-13 expression was examined by immunohistochemical, Western blot, and real-time RT-PCR analyses.
  
  
  RESULTS
  MMP-13 expression was highly up-regulated in MDA-MB-231 cells, and attachment of these cells to type I collagen and the induction of MMP-13 were down-regulated by treatment with integrin α1, α2 or β1 neutralizing antibodies. The attachment of MDA-MB-231 cells to type I collagen induced the activation of focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK). Inhibition of FAK and p38 MAPK down-regulated type I collagen-induced MMP-13 expression.
  
  
  CONCLUSIONS
  Our study indicates that metastatic breast cancer cells in the bone microenvironment attached to type I collagen, which stimulated integrins α1β1 and α2β1, via FAK and p38 MAPK pathways, to induce MMP13 expression and further osteolysis.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ibaragi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimo
authors.forename: Nur Mohammad Monsur
authors.initials: NM
authors.lastname: Hassan
authors.forename: Sachiko
authors.initials: S
authors.lastname: Isowa
authors.forename: Naito
authors.initials: N
authors.lastname: Kurio
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mandai
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kodama
authors.forename: Akira
authors.initials: A
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D039222:Integrin alpha1beta1 / Q000235:genetics / Q000378:metabolism*; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D039222:Integrin alpha1beta1; D038982:Integrin alpha2beta1; D012333:RNA, Messenger; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13