Basic fibroblast growth factor induces matrix metalloproteinase-13 via eRK MAP kinase-altered phosphorylation and sumoylation of Elk-1 in human adult articular chondrocytes

Hee Jeong Im, Andrew D. Sharrocks, Xia Lin, Dongyao Yan, Jaesung Kim, Andre J. Van Wijnen, Robert A. Hipskind

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)151-161
Number of pages11
JournalOpen Access Rheumatology: Research and Reviews
Volume1
Issue number1
StatePublished - Dec 1 2009

Keywords

  • Elk-1
  • MMP-13
  • Osteoarthritis
  • SUMO
  • bFGF

ASJC Scopus subject areas

  • Rheumatology

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