title: Limited efficacy of COX-2 inhibitors on nerve growth factor and metalloproteinases expressions in human synovial fibroblasts.
abstract: BACKGROUND
  Nerve growth factor (NGF) is associated with arthritic pain and metalloproteinases are implicated in collagen and aggrecan degradation. Although selective COX-2 inhibitors are recommended for the treatment of arthritic diseases, their effects on NGF and metalloproteinases remain unclear. This study investigated the regulations of NGF and metalloproteinases by selective COX-2 inhibitors in isolated human synovial cells.
  
  
  METHODS
  The isolated human synovial cells were stimulated with IL-1β in the presence of selective COX-2 inhibitors (NS-398 or celecoxib) with or without exogenous PGE2 or its receptor (EP1-4) agonists. The expressions of NGF, MMP-1, -3, -13, ADAMTS-4, and -5 were quantified by real-time PCR and their proteins were determined by Western blotting. The amount of PGE2 released was measured by enzyme-linked immunosorbent assay (ELISA).
  
  
  RESULTS
  The IL-1β inductions of NGF and MMP-1 and MMP-13 were augmented by the COX-2 inhibitors, whereas the inductions of ADAMTS-4 and ADAMTS-5 were inhibited. These actions were reversed by supplementing PGE2 or the EP4 agonist exogenously.
  
  
  CONCLUSIONS
  Our comprehensive analysis revealed that COX-2 inhibitors may be beneficial for suppressing aggrecan degradation and for reducing inflammatory pain by inhibiting PGE2 release, although they may have limited efficacy in suppressing collagen degradation and nerve growth. This study suggests the feedback roles of PGE2 in the negative regulation of NGF and MMP-1 and MMP-13 and the positive regulation of ADAMTS-4 and ADAMTS-5.
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yorifuji
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Electronic address: sawayasu@mac.com.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Sawaji
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Endo
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
authors.forename: Taiichi
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D015153:Blotting, Western; D000068579:Celecoxib / Q000494:pharmacology; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D045726:Metalloproteases / Q000187:drug effects* / Q000378:metabolism*; D015999:Multivariate Analysis; D020932:Nerve Growth Factor / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D013583:Synovial Membrane / Q000166:cytology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C502240:NGF protein, human; D020932:Nerve Growth Factor; D045726:Metalloproteases; D000068579:Celecoxib; D015232:Dinoprostone