title: Expression of cathepsin K messenger RNA in giant cells and their precursors in human osteoarthritic synovial tissues.
abstract: OBJECTIVE
  To investigate the expression of cathepsin K messenger RNA (mRNA) in the giant cells found in human osteoarthritic (OA) synovium and associated reparative connective tissues, and to compare this with mRNA expression of cathepsins B, L, and S, which are cysteine proteases known to be highly expressed by cells of the monocyte/macrophage lineage.
  
  
  METHODS
  Sections of human OA synovium were processed for in situ hybridization and probed for cathepsins K, B, L, and S. Serial sections were reacted for tartrate-resistant acid phosphatase (TRAP) and nonspecific esterase (NSE) activity, which are selective markers for the osteoclast and cells of the macrophage/monocyte lineage, respectively.
  
  
  RESULTS
  At 3 sites of monocyte infiltration/giant cell formation (granulation tissue, the intimal and subintimal synovial layers, and deep stroma extending to the periphery of osteophytic tissue), both TRAP-positive mono- and multinucleated cells and TRAP-negative, NSE-positive mononuclear precursors were identified. Cells containing both enzyme activities were also found, potentially indicating an intermediate stage of differentiation. The TRAP-positive mononuclear/giant cells, and the occasional NSE-positive precursor, expressed an intense signal for cathepsin K mRNA, but did not express cathepsins B, L, and S. In contrast, the deep zone of phagocytic-like cells adjacent to sites of ossification expressed high levels of mRNA for cathepsins L, B, and S as well as cathepsin K mRNA.
  
  
  CONCLUSIONS
  Giant cells that form within OA synovial tissue express high levels of cathepsin K mRNA. It appears that cathepsin K acts principally to digest the bone (and cartilage) fragments sheered from the joint surface during OA. The high TRAP activity and the undetectable expression of the macrophage-associated degradative proteases (cathepsins B, L, and S) by synovial giant cells strengthens the hypothesis that cathepsin K is the primary protease involved in bone degradation. At sites of synovial osteogenesis, a population of phagocytic-like cells expressed TRAP and cathepsins B, L, S, and K, and may represent blood-derived macrophages pushed toward an osteoclast phenotype.
authors.affiliation: SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Dodds
authors.forename: J R
authors.initials: JR
authors.lastname: Connor
authors.forename: F H
authors.initials: FH
authors.lastname: Drake
authors.forename: M
authors.initials: M
authors.lastname: Gowen
mesh_terms: D002401:Cathepsin B / Q000235:genetics; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics*; D003546:Cysteine Endopeptidases / Q000235:genetics; D010450:Endopeptidases; D004792:Enzyme Precursors / Q000032:analysis / Q000235:genetics; D006097:Granulation Tissue / Q000201:enzymology; D006801:Humans; D008264:Macrophages / Q000201:enzymology; D009283:Naphthol AS D Esterase; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*
chemical_list: D004792:Enzyme Precursors; D012333:RNA, Messenger; D009283:Naphthol AS D Esterase; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K