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,^1–4 Andrew D Sharrocks,⁵ Xia Lin,⁶ Dongyao Yan,¹ Jaesung Kim,¹ Andre J van Wijnen,⁷ Robert A Hipskind⁸

¹Departments of Biochemistry, ²Internal Medicine, ³Section of Rheumatology, Orthopedic Surgery, ⁴Rush University Medical Center, and Department of Bioengineering; University of Illinois at Chicago, IL USA; ⁵Faculty of Life Sciences, University of Manchester, Oxford Rd, Manchester, UK; ⁶Michael D DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA; ⁷Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA; ⁸Institute De Genetique Moleculaire de Montpellier, France

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.

Keywords: osteoarthritis, MMP-13, bFGF, SUMO, Elk-1