title: Increased expression and processing of ADAM 12 (meltrin-alpha) in osteolysis associated with aseptic loosening of total hip replacement implants.
abstract: OBJECTIVE
  To assess the expression and processing of a disintegrin and metalloproteinase, ADAM 12 (meltrin-alpha), in the formation of multinuclear cells. Methods. In situ hybridization, immunohistochemical staining, and Western blotting of interface membrane around loosened total hip replacement implants. Macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) costimulation of human monocytes followed by FACS, immunofluorescence staining, Western blotting, and bone resorption assay.
  
  
  RESULTS
  ADAM 12 mRNA-containing mononuclear cells were often seen in a close spatial relationship with ADAM 12-positive multinuclear cells. Morphometric analysis of ADAM 12 disclosed that 53% +/- 2% of all interface cells were ADAM 12-positive compared to 5% +/- 1% in controls (p < 0.001). M-CSF and RANKL were richly present in interface tissue around loosening implants. Upon M-CSF and RANKL costimulation of human monocytes in vitro, the ADAM 12 staining pattern changed over time, and ADAM 12-positive cells formed large mono-, bi-, and multinuclear cells at Day 7 and many multinuclear giant cells and/or osteoclasts at Day 14. Western blot disclosed 90 kDa latent ADAM 12L but also the metalloproteinase-cleaved, fusion-active 60 kDa form transiently just before the burst of fusion.
  
  
  CONCLUSIONS
  ADAM 12, well recognized for participation in cell-cell fusion in myoblast formation, is upregulated and processed upon formation of multinuclear giant cells and osteoclasts. It may play a role in formation of giant cells and osteoclasts around loosened total hip replacement implants.
authors.affiliation: Department of Medicine/Invärtes medicin, Biomedicum, FIN-00029 Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Ma
authors.forename: Mari
authors.initials: M
authors.lastname: Ainola
authors.forename: Mikko
authors.initials: M
authors.lastname: Liljeström
authors.forename: Seppo
authors.initials: S
authors.lastname: Santavirta
authors.forename: Praseet
authors.initials: P
authors.lastname: Poduval
authors.forename: Desheng
authors.initials: D
authors.lastname: Zhao
authors.forename: Tong
authors.initials: T
authors.lastname: Chen
authors.forename: Yrjö T
authors.initials: YT
authors.lastname: Konttinen
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072199:ADAM12 Protein; D000368:Aged; D000369:Aged, 80 and over; D019644:Arthroplasty, Replacement, Hip; D001862:Bone Resorption; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D015726:Giant Cells / Q000378:metabolism; D006622:Hip Prosthesis / Q000009:adverse effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010014:Osteolysis / Q000201:enzymology* / Q000473:pathology; D011475:Prosthesis Failure; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human