title: Hyaluronan Oligosaccharides Induce MMP-1 and -3 via Transcriptional Activation of NF-κB and p38 MAPK in Rheumatoid Synovial Fibroblasts.
abstract: OBJECTIVE
  To explore the effect of hyaluronan oligosaccharides (HAoligos) on interactions between HA and its principal receptor, CD44, in rheumatoid synovial fibroblasts (RSFs) and matrix metalloproteinase (MMP) production.
  
  
  METHODS
  RSFs were isolated from rheumatoid synovial tissue. HA distribution was visualized by immunocytochemistry. MMP-1 and MMP-3 induction was analyzed by real-time RT-PCR and immunoblotting. The interaction between HAoligos and their MMP-producing receptors was tested by blocking with anti-CD44 and anti-Toll-like receptor 4 (TLR-4). Phosphorylation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) was analyzed by immunoblotting.
  
  
  RESULTS
  Endogenous HA decreased after treatment with HAoligos, while MMP-1 and MMP-3 expression increased in a dose-dependent manner. Pretreatment with anti-CD44 or anti-TLR-4 antibody significantly reduced the effect of HAoligos on MMP-1 and MMP-3 mRNA expression. NF-κB and p38 MAPK phosphorylation was enhanced by HAoligos pretreated with anti-TLR-4, and HAoligo-induced MMP production was blocked with an inhibitor of NF-κB and p38 MAPK pathways.
  
  
  CONCLUSIONS
  Disruptive changes in CD44-HA interactions by HAoligos enhanced MMP-1 and MMP-3 production via activation of NF-κB and p38 MAPK signaling pathways in RSFs.
authors: Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Masahiro
authors: M
authors: Hanabayashi
authors: Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Nobunori
authors: N
authors: Takahashi
authors: Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Yasumori
authors: Y
authors: Sobue
authors: Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Shinya
authors: S
authors: Hirabara
authors: Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Naoki
authors: N
authors: Ishiguro
authors: Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Toshihisa
authors: T
authors: Kojima
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid / Q000378:metabolism; D015151:Immunoblotting; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009844:Oligosaccharides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; D016328:NF-kappa B; D009844:Oligosaccharides; D006820:Hyaluronic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1