title: Regulation of matrixmetalloproteinase-3 and matrixmetalloproteinase-13 by SUMO-2/3 through the transcription factor NF-κB.
abstract: OBJECTIVE
  Based on previous data that have linked the small ubiquitin-like modifier-1 (SUMO-1) to the pathogenesis of rheumatoid arthritis (RA), we have investigated the expression of the highly homologous SUMO family members SUMO-2/3 in human RA and in the human tumour necrosis factor α transgenic (hTNFtg) mouse model of RA and studied their role in regulating disease specific matrixmetalloproteinases (MMPs).
  
  
  METHODS
  Synovial tissue was obtained from RA and osteoarthritis (OA) patients and used for histological analyses as well as for the isolation of synovial fibroblasts (SFs). The expression of SUMO-2/3 in RA and OA patients as well as in hTNFtg and wild type mice was studied by PCR, western blot and immunostaining. SUMO-2/3 was knocked down using small interfering RNA in SFs, and TNF-α induced MMP production was determined by ELISA. Activation of nuclear factor-κB (NF-κB) was determined by a luciferase activity assay and a transcription factor assay in the presence of the NF-κB inhibitor BAY 11-7082.
  
  
  RESULTS
  Expression of SUMO-2 and to a lesser extent of SUMO-3 was higher in RA tissues and RASFs compared with OA controls. Similarly, there was increased expression of SUMO-2 in the synovium and in SFs of hTNFtg mice compared with wild type animals. In vitro, the expression of SUMO-2 but not of SUMO-3 was induced by TNF-α. The knockdown of SUMO-2/3 significantly increased the TNF-α and interleukin (IL)-1β induced expression of MMP-3 and MMP-13, accompanied by increased NF-κB activity. Induction of MMP-3 and MMP-13 was inhibited by blockade of the NF-κB pathway. TNF-α and IL-1β mediated MMP-1 expression was not regulated by SUMO-2/3.
  
  
  CONCLUSIONS
  Collectively, we show that despite their high homology, SUMO-2/3 are differentially regulated by TNF-α and selectively control TNF-α mediated MMP expression via the NF-κB pathway. Therefore, we hypothesise that SUMO-2 contributes to the specific activation of RASF.
authors: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, , Muenster, Germany.
authors: Svetlana
authors: S
authors: Frank
authors: Marvin A
authors: MA
authors: Peters
authors: Corinna
authors: C
authors: Wehmeyer
authors: Simon
authors: S
authors: Strietholt
authors: Christina
authors: C
authors: Koers-Wunrau
authors: Jessica
authors: J
authors: Bertrand
authors: Marianne
authors: M
authors: Heitzmann
authors: Anja
authors: A
authors: Hillmann
authors: Joanna
authors: J
authors: Sherwood
authors: Christine
authors: C
authors: Seyfert
authors: Steffen
authors: S
authors: Gay
authors: Thomas
authors: T
authors: Pap
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology*; D010003:Osteoarthritis / Q000378:metabolism; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D014452:Ubiquitins / Q000502:physiology
chemical_list: D016328:NF-kappa B; C117909:SUMO2 protein, human; C515972:SUMO2 protein, mouse; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C117908:Sumo3 protein, mouse; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D014452:Ubiquitins; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3
keywords: Fibroblasts; Rheumatoid Arthritis; TNF-alpha