title: The role of cyclooxygenase-2, interleukin-1β and fibroblast growth factor-2 in the activation of matrix metalloproteinase-1 in sheared-chondrocytes and articular cartilage.
abstract: MMP-1 expression is detected in fluid shear stress (20 dyn/cm(2))-activated and osteoarthritic human chondrocytes, however, the precise mechanisms underlying shear-induced MMP-1 synthesis remain unknown. Using primary chondrocytes and T/C-28a2 chondrocytic cells as model systems, we report that prolonged application of high fluid shear to human chondrocytes induced the synthesis of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and fibroblast growth factor-2 (FGF-2), which led to a marked increase in MMP-1 expression. IL-1β, COX-2-dependent PGE2 activated the PI3-K/AKT and p38 signaling pathways, which were in turn responsible for MMP-1 synthesis via NF-κB- and c-Jun-transactivating pathways. Prolonged shear stress exposure (>12 h) induced 15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) synthesis. Although 15d-PGJ2 suppressed PI3-K/AKT and p38 signaling pathways, it stimulated MMP-1 expression via activating heme oxygenase 1 (HO-1). The critical role of COX-2 in regulating MMP-1 expression in articular cartilage in vivo was demonstrated using COX-2(+/-) transgenic mice in the absence or presence of rofecoxib oral administration. These findings provide novel insights for developing therapeutic strategies to combat OA.
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Guan
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819.
authors.forename: Jing-Wen
authors.initials: JW
authors.lastname: Guo
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: 1] Department of Chemical and Biomolecular Engineering [2] Johns Hopkins Institute for NanoBioTechnology [3] Johns Hopkins Physical Sciences-Oncology Center [4] Center of Cancer Nanotechonology Excellence, The Johns Hopkins University, Baltimore, Maryland, United States of America, 21218.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Konstantopoulos
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819.
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D033081:Shear Strength; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C477819:15-deoxyprostaglandin J2; D053583:Interleukin-1beta; D016328:NF-kappa B; D016222:Fibroblast Growth Factor 2; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone; D015230:Prostaglandin D2