Basic Fibroblast Growth Factor Stimulates Matrix Metalloproteinase-13 via the Molecular Cross-talk between the Mitogen-activated Protein Kinases and Protein Kinase Cδ 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) ␦ played a key role in the MMP-13 stimulation. Indeed, PKC␦ is the only isoform associated with MMP-13 stimulation among the PKC isoforms tested. PKC␦ controls the bFGF response by regulating multiple MAPK pathways. Our results suggest that PKC␦ 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 PKC␦ signaling may contribute to the etiology of osteoarthritis in human patients. Osteoarthritis (OA)2 involves the progressive destruction of the cartilage extracellular matrix (ECM) by a pathological imbalance in the normal metabolic functions of articular chondrocytes. Under normal conditions, chondrocytes maintain a dynamic equilibrium between synthesis and degradation of ECM components. Although the causative events in the etiology of OA remain to be clearly defined, OA is characterized by a disruption of matrix equilibrium leading to progressive loss of cartilage tissue and clonal expansion of cells in the depleted regions. In the early stages of OA, cells respond with a transient induction of matrix synthesis (e.g. increases in the expression and/or protein secretion of insulin-like growth factor-1 (IGF-1) and bone morphogenetic protein 7 (BMP7 or OP-1)). This de novo ECM synthesis cannot overcome the concurrent catabolic processes (1, 2) that involve the excess production of matrixdegrading enzymes, including matrix metalloproteinases (MMPs), aggrecanases, and other proteinases by chondrocytes. The resulting degradation of cartilage ECM may exacerbate the imbalance by enhancing the local activity of systemic regulatory factors, including growth factors and cytokines.Matrix metalloproteinase-13 (MMP-13 or collagenase-3) is the most potent enzyme that degrades type II collagen (the...

Protein Kinase C-δ Transactivates Platelet-derived Growth Factor Receptor-α in Mechanical Strain-induced Collagenase 3 (Matrix Metalloproteinase-13) Expression by Osteoblast-like Cells

“…On the other hand, the results of inhibition by rottlerin or ⌬PKC-␦ on the mechanical straininduced p42/p44 MAPK phosphorylation suggested a mechanism of the molecular cross-talk between MAPK and PKC-␦ (30). In fact, we also found that cross-talk occurred between PDGFR-␣/PI3K and p42/p44 MAPK pathways.…”

“…For example, the PKC-␦ activation is found to be a principle rate-limiting event in the basic fibroblast growth factor-dependent stimulation of MMP-13 in human articular chondrocytes (30), whereas the stimulation of the PDGFR-␤ signaling pathway activates PKC-␦ in the PDGFR-␤-mediated-monocytic differentiation (31). Furthermore, the stretch-induced expression of vascular endothelial growth factor appeared to be mediated by the PI3K/PKCpathway (32).…”

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

“…Further evidence suggests that bFGF is pathologically associated with joint destruction via upregulation of MMPs and aggrecanases, as well as the stimulation of reactive oxygen species such as nitric oxide and superoxide anion (well-known catabolic factors for articular cartilage and spine discs), revealing the potential catabolic activity of bFGF in articular cartilage (Qu et al, 1995;Tchetina et al, 2005;Im et al, 2007;Muddasani et al, 2007, Muddasani et al, 2008. In patients with degenerative joint disease after traumatic injury, for example, the expression of bFGF is highly upregulated in synovial tissues of arthritic joints compared to normal joints (Cameron et al, 1994;Qu et al, 1995).…”

“…Stimulation of human articular chondrocytes isolated from knee and ankle cartilage (both normal and OA) with bFGF was shown to upregulate MMP-13 and ADAMTS-4 and -5 expression (aggrecanases), inhibit PG production and synthesis in a time and dose-dependent manner, antagonize the activity of anabolic factors BMP7 and IGF-1, and stimulate pro-inflammatory cytokines such as IL-1 and TNF-α, elucidating the degradative effects of bFGF on articular cartilage homeostasis Im et al, 2008;Im et al, 2007;Muddasani et al, 2007). Others have reported similar findings in cultured human chondrosarcoma cells (Uria et al, 1998) and osteoblasts (Varghese et al, 2000), revealing that treatment with bFGF increases MMP-13 expression in a dose and time-dependent manner.…”

“…In degenerative states, however, there is a disruption of matrix equilibrium leading to progressive loss of cartilage tissue and clonal expansion of cells in the depleted regions. Chondrocyte metabolism is unbalanced due to excessive production of catabolic factors, including matrix metalloproteases (MMPs), aggrecanases (ADAMTS), and other cytokines and growth factors released by chondrocytes that aid in the destruction of PGs and the ECM (Im et al, 2008;Im et al, 2007;Muddasani et al, 2007). For example, as matrix equilibrium shifts to a pro-catabolic state with advancing degeneration in articular cartilage, collagenasemediated degradation of type II collagen becomes more prominent (Hollander et al, 1994;Billinghurst et al, 1997).…”