Fibroblast growth factor control of cartilage homeostasis

Abstract

Osteoarthritis (OA) and degenerative disc disease (DDD) are similar diseases involving the breakdown of cartilage tissue, and a better understanding of the underlying biochemical processes involved in cartilage degeneration may allow for the development of novel biologic therapies aimed at slowing the disease process. Three members of the fibroblast growth factor (FGF) family, FGF-2, FGF-18, and FGF-8, have been implicated as contributing factors in cartilage homeostasis. The role of FGF-2 is controversial in both articular and intervertebral disc (IVD) cartilage as it has been associated with species- and age-dependent anabolic or catabolic events. Recent evidence suggests that FGF-2 selectively activates FGF receptor 1 (FGFR1) to exert catabolic effects in human articular chondrocytes and IVD tissue via upregulation of matrix-degrading enzyme production, inhibition of extracellular matrix (ECM) accumulation and proteoglycan synthesis, and clustering of cells characteristic of arthritic states. FGF-18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating the FGFR3 pathway, inducing ECM formation and chondrogenic cell differentiation, and inhibiting cell proliferation. These changes result in dispersed chondrocytes or disc cells surrounded by abundant matrix. The role of FGF-8 has recently been identified as a catabolic mediator in rat and rabbit articular cartilage, but its precise biological impact on human adult articular cartilage or IVD tissue remains unknown. The available evidence reveals the promise of FGF-2/FGFR1 antagonists, FGF-18/FGFR3 agonists, and FGF-8 antagonists (i.e., anti-FGF-8 antibody) as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future.

Fig. 1

Schematic model of FGF-2 and FGF-18 signaling pathways in articular cartilage and IVD. A: FGF-2 binds to both FGFR1 and FGFR3 with high affinity. The phosphorylation of FGFR1 triggers Ras and PKCδ activation, which converge on the Raf-MEK1/2–ERK1/2 axis. Active ERK1/2 utilizes at least two critical transcription factors, Elk-1 and RUNX2, to upregulate an array of genes including MMP-13, ADAMTS-4, ADAMTS-5, COL10A1, and VEGF. In parallel, PKCδ also activates p38 and JNK, which act in concert with ERK1/2 to promote ECM degeneration and inhibition of anabolic activities. The binding of FGF-2 to FGFR3 may counteract the FGF-2-induced catabolic pathway, similar to that utilized by FGF-18. Therefore, the ratio of FGFR3/FGFR1 is a key to the biological outcome of FGF-2. B: FGF-18 specifically binds to FGFR3, which in turn activates MAPK and Akt pathways. The MAPK pathway differs from those in FGF-2 signaling, because neither Elk-1 nor RUNX2 is activated as a result. The Akt pathway may enhance PG deposition and account for the anabolic activity of FGF-18.