title: SERPINE2 Inhibits IL-1α-Induced MMP-13 Expression in Human Chondrocytes: Involvement of ERK/NF-κB/AP-1 Pathways.
abstract: OBJECTIVE
  Osteoarthritis (OA) is a chronic joint disease, characterized by a progressive loss of articular cartilage. During OA, proinflammatory cytokines, such as interleukin IL-1, induce the expression of matrix metalloproteinases (MMPs) in chondrocytes, contributing thus to the extracellular matrix (ECM) degradation. Members of Serpine family, including plasminogen activator inhibitors have been reported to participate in ECM regulation. The aim of this study was to assess the expression of serpin peptidase inhibitor clade E member 2 (SERPINE2), under basal conditions and in response to increasing doses of IL-1α, in human cultured chondrocytes. We also examined the effects of SERPINE2 on IL-1α-induced MMP-13 expression. For completeness, the signaling pathway involved in this process was also explored.
  
  
  METHODS
  SERPINE2 mRNA and protein expression were evaluated by RT-qPCR and western blot analysis in human T/C-28a2 cell line and human primary chondrocytes. These cells were treated with human recombinant SERPINE2, alone or in combination with IL-1α. ERK 1/2, NFκB and AP-1 activation were assessed by western blot analysis.
  
  
  RESULTS
  Human cultured chondrocytes express SERPINE2 in basal condition. This expression increased in response to IL-1α stimulation. In addition, recombinant SERPINE2 induced a clear inhibition of MMP-13 expression in IL-1α-stimulated chondrocytes. This inhibitory effect is likely regulated through a pathway involving ERK 1/2, NF-κB and AP-1.
  
  
  CONCLUSIONS
  Taken together, these data demonstrate that SERPINE2 might prevent cartilage catabolism by inhibiting the expression of MMP-13, one of the most relevant collagenases, involved in cartilage breakdown in OA.
authors: SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), the NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain; University of Naples Federico II, Dept. of Pharmacy, 80138, Naples, Italy.
authors: Anna
authors: A
authors: Santoro
authors: SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), the NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
authors: Javier
authors: J
authors: Conde
authors: SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), the NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
authors: Morena
authors: M
authors: Scotece
authors: SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), the NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain; Department of Molecular and Cellular Biology, University of Coruña (UDC), A Coruña, Spain.
authors: Vanessa
authors: V
authors: Abella
authors: SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), the NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
authors: Ana
authors: A
authors: Lois
authors: SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), the NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
authors: Veronica
authors: V
authors: Lopez
authors: SERGAS (Servizo Galego de Saude), Division of Orthopaedics Surgery and Traumatology, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
authors: Jesus
authors: J
authors: Pino
authors: SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), the NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
authors: Rodolfo
authors: R
authors: Gomez
authors: University of Santiago de Compostela, Department of Medicine and SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), Division of Rheumatology, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
authors: Juan J
authors: JJ
authors: Gomez-Reino
authors: SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), the NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
authors: Oreste
authors: O
authors: Gualillo
mesh_terms: D002358:Cartilage, Articular / Q000254:growth & development / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D053582:Interleukin-1alpha / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000235:genetics; D010003:Osteoarthritis / Q000235:genetics* / Q000503:physiopathology; D061251:Primary Cell Culture; D058258:Serpin E2 / Q000096:biosynthesis* / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D053582:Interleukin-1alpha; D016328:NF-kappa B; C545486:SERPINE2 protein, human; D058258:Serpin E2; D018808:Transcription Factor AP-1; D053509:Matrix Metalloproteinase 13