title: Basic fibroblast growth factor induces matrix metalloproteinase-13 via ERK MAP kinase-altered phosphorylation and sumoylation of Elk-1 in human adult articular chondrocytes.
abstract: Degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) and release of basic fibroblast growth factor (bFGF) are principal aspects of the pathology of osteoarthritis (OA). ECM disruption leads to bFGF release, which activates the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway and its downstream target the Ets-like transcription factor Elk-1. Previously we demonstrated that the bFGF-ERK-Elk-1 signaling axis is responsible for the potent induction of MMP-13 in human primary articular chondrocytes. Here we report that, in addition to phosphorylation of Elk-1, dynamic posttranslational modification of Elk-1 by small ubiquitin-related modifier (SUMO) serves as an important mechanism through which MMP-13 gene expression is regulated. We show that bFGF activates Elk-1 mainly through the ERK pathway and that increased phosphorylation of Elk-1 is accompanied by decreased conjugation of SUMO to Elk-1. Reporter gene assays reveal that phosphorylation renders Elk-1 competent for induction of MMP-13 gene transcription, while sumoylation has the opposite effect. Furthermore, we demonstrate that the SUMO-conjugase Ubc9 acts as a key mediator for Elk-1 sumoylation. Taken together, our results suggest that sumoylation antagonizes the phosphorylation-dependent transactivation capacity of Elk-1. This attenuates transcription of its downstream target gene MMP-13 to maintain the integrity of cartilage ECM homeostasis.
authors: Departments of Biochemistry; Internal Medicine; Section of Rheumatology, Orthopedic Surgery; Rush University Medical Center, and Department of Bioengineering, University of Illinois at Chicago, IL USA.
authors: Hee-Jeong
authors: HJ
authors: Im
authors: Faculty of Life Sciences, University of Manchester, Oxford Rd, Manchester, UK.
authors: Andrew D
authors: AD
authors: Sharrocks
authors: Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors: Xia
authors: X
authors: Lin
authors: Departments of Biochemistry.
authors: Dongyao
authors: D
authors: Yan
authors: Departments of Biochemistry.
authors: Jaesung
authors: J
authors: Kim
authors: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Andre J
authors: AJ
authors: van Wijnen
authors: Institute De Genetique Moleculaire de Montpellier, France.
authors: Robert A
authors: RA
authors: Hipskind
keywords: Elk-1; MMP-13; SUMO; bFGF; osteoarthritis