Basic fibroblast growth factor activates the MAPK and NFkappaB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes.
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 Cdelta-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 NFkappaB and induces MMP-13 expression upon activation of the NFkappaB signaling pathway. Taken together, our results suggest that elevated expression of MMP-13 occurs through Elk-1 activation of both MAPK and NFkappaB 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.
Muddasani
Prasuna
P
Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
Norman
Jim C
JC
Ellman
Michael
M
van Wijnen
Andre J
AJ
Im
Hee-Jeong
HJ
D000328:Adult; D002358:Cartilage, Articular / Q000166:cytology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology*; D016895:Culture Media, Serum-Free; D018274:Electroporation; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
D016895:Culture Media, Serum-Free; D016328:NF-kappa B; D050807:ets-Domain Protein Elk-1; D016222:Fibroblast Growth Factor 2; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13