title: Transmigration: a new property of mature multinucleated osteoclasts.
abstract: Even though it is assumed that multinucleated osteoclasts are migrating cells on the bone surface to be resorbed, we show that they can also selectively transmigrate through layers of cells usually found in the bone microenvironment. This activity is associated with c-src and MMPs and can be stimulated by bone metastatic breast cancer cells, a process blocked by bisphosphonate treatment.
  
  
  BACKGROUND
  Osteoclasts have an hematopoietic origin and are bone-resorbing cells. Monocytic precursors migrate to the bone surface where they fuse to form multinucleated osteoclasts able to migrate over the bone surface. We studied whether multinucleated osteoclasts were also able to transmigrate through tissues.
  
  
  METHODS
  Murine spleen-derived and green fluorescent protein (GFP)-Raw derived osteoclasts were seeded on osteoblasts and several other cell types. The cells were fixed for 20 minutes, 4 or 12 h after osteoclast seeding, and stained with phalloidin to visualize actin using confocal microscopy. Drugs such as PP2 and GM6001, inhibitors of c-src and matrix metalloproteinases (MMPs), respectively, and risedronate were used to determine osteoclast transmigration regulating factors.
  
  
  RESULTS
  We observed by confocal microscopy that multinucleated osteoclasts specifically transmigrate through confluent layers of various cell types present in the bone microenvironment in vitro. This is an efficient process associated with c-src and MMPs but is independent of podosomes. Moreover, conditioned medium from bone metastatic breast cancer cells stimulates osteoclast transmigration in vitro, a process inhibited by bisphosphonate treatment.
  
  
  CONCLUSIONS
  Our data describe a new property of mature multinucleated osteoclasts to transmigrate through various cell types. The ability to control this highly regulated osteoclast transmigration process may offer new therapeutic strategies for bone diseases associated with an imbalance in bone remodeling caused by excessive osteoclast resorption.
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, Lyon, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saltel
authors.forename: Anne
authors.initials: A
authors.lastname: Chabadel
authors.forename: Yingshe
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Lafage-Proust
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
authors.forename: Pierre
authors.initials: P
authors.lastname: Jurdic
authors.forename: Edith
authors.initials: E
authors.lastname: Bonnelye
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D015726:Giant Cells / Q000166:cytology / Q000201:enzymology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: C412373:AG 1879; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D011743:Pyrimidines; D016392:Proto-Oncogene Proteins pp60(c-src); D020782:Matrix Metalloproteinases