The role of fibroblast growth factor-2 in articular cartilage degradation

Osteoarthritis (OA) is the most common form of joint disease and a leading cause of physical disability woridwide. Cartilage degradation in OA is due to an imbalance between synthesis and degradation of the extracellular matrix. Recent work from our laboratory has shown that the heparin-binding growth factor fibroblast growth factor2 (FGF-2) mediates key responses in cartilage following mechanical trauma and loading. It has also been shown that FGF-2 is localised within the pericellular matrix, attached to the heparan sulphate proteoglycan perlecan. The spatial modulator of chondrocyte function. The primary aim of this research was to define the role of FGF-2 in cartilage degradation in vivo. Mice with deletion of Fgf2, whilst morphologically indistinguishable from wild-type animals, exhibited accelerated spontaneous and surgically-induced OA. Surgically-induced OA in Fgf2 mice was suppressed to wild type levels by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2 mice was associated with increased expression of ADAMTS-5, the key murine aggrecanase, but not other matrix metalloproteinases. Explants from Fgf2 mice showed increased aggrecanolysis and ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motif, type 5; aggrecanase-2) gene expression following interleukin-1 (IL-1) stimulation, and exogenous FGF-2 suppressed IL-1 induced aggrecanolysis in wild-type explants. These data identify FGF-2 as a novel endogenous chondroprotective agent, and as an inhibitor of aggrecan breakdown acting through suppression of ADAMTS-5.EThOS - Electronic Theses Online ServiceGBUnited Kingdo