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

Abstract

Two members of the fibroblast growth factor (FGF) family, basic FGF (bFGF) and FGF-18, have been implicated in the regulation of articular and intervertebral disc (IVD) cartilage homeostasis. Studies on bFGF from a variety of species have yielded contradictory results with regards to its precise role in cartilage matrix synthesis and degradation. In contrast, FGF-18 is a well-known anabolic growth factor involved in chondrogenesis and articular cartilage repair. In this review, we examined the biological actions of bFGF and FGF-18 in articular and IVD cartilage, the specific cell surface receptors bound by each factor, and the unique signaling cascades and molecular pathways utilized to exert their biological effects. Evidence suggests that bFGF selectively activates FGF receptor 1 (FGFR1) to exert degradative effects in both human articular chondrocytes and IVD tissue via upregulation of matrix-degrading enzyme activity, inhibition of matrix production, and increased cell proliferation resulting in clustering of cells seen in arthritic states. FGF-18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating FGFR3, increasing matrix formation and cell differentiation while inhibiting cell proliferation, leading to dispersed cells surrounded by abundant matrix. The results from in vitro and in vivo studies suggest the potential usefulness of bFGF and FGFR1 antagonists, as well as FGF-18 and FGFR3 agonists, as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future.

Figure 1

Summary of bFGF-activation of multiple signaling pathways associated with articular cartilage degradation.

Figure 2

The PKCδ pathway acts as an upstream regulator for NFκB and MAPK (ERK, JNK, and p38) pathways involved in the bFGF-mediated phosphorylation of Elk-1, resulting in increased MMP-13 transcription.

Figure 3

Comparison of bFGF and FGF-18 in adult articular cartilage and/or IVD homeostasis. Basic FGF mainly activates FGFR1 while FGF-18 activates FGFR3 to exert distinctive biological effects in both adult articular cartilage and IVD.