Basic fibroblast growth factor activates the MAPK and NF kappa B pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes

Muddasani, P., Norman, J. , Ellman, M., van Wijnen, A. and Im, H. (2007) Basic fibroblast growth factor activates the MAPK and NF kappa B pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes. Journal of Biological Chemistry, 282(43), pp. 31409-31421. (doi: 10.1074/jbc.M706508200)

Abstract

The pathology of joint destruction is associated with elevated production of basic fibroblast growth factor (bFGF) and matrix metalloproteinase-13 (MMP-13). In osteoarthritic joint disease, expression of bFGF and MMP-13 in chondrocytes and their release into the synovial fluid are significantly increased. We have previously found that the capacity for cartilage repair in human adult articular chondrocytes is severely compromised by minimal exposure to bFGF because bFGF reduces responsiveness to bone morphogenetic protein-7 and insulin-like growth factor-1 and induces MMP-13 through protein kinase C delta-dependent activation of multiple mitogen-activated protein kinase (MAPK) signaling pathways. Here we show using biochemical and molecular approaches that transcription factor Elk-1, a direct downstream target of MAPK, is a critical transcriptional activator of of MMP-13 by bFGF in human articular chondrocytes. We also provide evidence that Elk-1 is a direct target of NF kappa B and induces MMP-13 expression upon activation of the NF kappa B signaling pathway. Taken together, our results suggest that elevated expression of MMP-13 occurs through Elk-1 activation of both MAPK and NF kappa B signaling pathways, thus revealing a two-pronged biological mechanism by which bFGF controls the production of catabolic enzymes that are associated with excessive degradation of the cartilage matrix in degenerative joint diseases such as osteoarthritis.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Norman, Professor James
• Authors: Muddasani, P., Norman, J., Ellman, M., van Wijnen, A., and Im, H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Biological Chemistry
• Journal Abbr.: J Biol Chem.
• Publisher: American Society for Biochemistry and Molecular Biology, Inc.
• ISSN: 0021-9258
• ISSN (Online): 1083-351X