title: Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase Cdelta pathways in human adult articular chondrocytes.
abstract: Excessive release of basic fibroblast growth factor (bFGF) during loading and/or injury of the cartilage matrix may contribute to the onset or progression of osteoarthritis. This pathological role may be related to the ability of bFGF to decrease proteoglycan synthesis and to antagonize the activity of anabolic growth factors in cartilage such as insulin-like growth factor-1 and bone morphogenetic protein 7 (BMP7 or OP-1). Matrix metalloproteinase-13 (MMP-13), a catabolic cartilage-degrading enzyme, is dramatically up-regulated by inflammatory cytokines or by fibronectin fragments in articular chondrocytes. In this study, we investigated MMP-13 production by bFGF using human articular chondrocytes. Endogenous concentration of bFGF in synovial fluids collected from arthritis patients and asymptomatic subjects showed a good linear correlation with the endogenous levels of MMP-13. bFGF stimulation of MMP-13 was mediated at the transcriptional level and, at least in part, by stimulation of interleukin-1 production. Also, our findings suggest that bFGF stimulation of MMP-13 required the activation of multiple MAPKs (ERK, p38, and JNK) by bFGF, and more importantly, bFGF activation of protein kinase C (PKC) delta played a key role in the MMP-13 stimulation. Indeed, PKCdelta is the only isoform associated with MMP-13 stimulation among the PKC isoforms tested. PKCdelta controls the bFGF response by regulating multiple MAPK pathways. Our results suggest that PKCdelta activation is a principal rate-limiting event in the bFGF-dependent stimulation of MMP-13 in human adult articular chondrocytes. We propose that deregulation of cross-talk between MAPK and PKCdelta signaling may contribute to the etiology of osteoarthritis in human patients.
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA. Hee-Jeong_Sampen@rush.edu
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
authors.forename: Prasuna
authors.initials: P
authors.lastname: Muddasani
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Schmid
authors.forename: Joel A
authors.initials: JA
authors.lastname: Block
authors.forename: Francesca
authors.initials: F
authors.lastname: Davis
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Richard F
authors.initials: RF
authors.lastname: Loeser
mesh_terms: D000328:Adult; D001158:Arteries / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013582:Synovial Fluid / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D016222:Fibroblast Growth Factor 2; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13