Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

OBJECTIVE: Articular chondrocytes are surrounded by an extracellular pool of fibroblast growth factor 2 (FGF-2). We undertook this study to investigate the possible role of FGF-2 in aggrecan catabolism by aggrecanase in human articular cartilage. METHODS: Aggrecan catabolism was induced by interleukin-1alpha (IL-1alpha) in normal human articular cartilage and assessed by measuring the release of glycosaminoglycan (GAG) and aggrecanase-dependent fragments by Western blotting with antibodies against neoepitopes. ADAMTS-4 and ADAMTS-5 messenger RNA (mRNA) expression was measured by quantitative real-time reverse transcriptase-polymerase chain reaction. Production of matrix metalloproteinases (MMPs) 1, 3, and 13 and tissue inhibitors of metalloproteinases (TIMPs) 1 and 3 was measured by Western blotting. IL-6 and IL-8 were measured by enzyme-linked immunosorbent assay. Proteoglycan synthesis was monitored by 35S-sulfate incorporation. RESULTS: IL-1alpha caused cleavage of aggrecan in cultured human articular cartilage explants, with release of GAG and aggrecan fragments containing ARGS and AGEG neoepitopes. This was inhibited by FGF-2 (1-100 ng/ml). Tumor necrosis factor alpha and retinoic acid also stimulated release of neoepitope, and this was also suppressed by FGF-2. IL-1alpha induced ADAMTS-4 and ADAMTS-5 mRNA in primary human chondrocytes, and this was inhibited by FGF-2. IL-1alpha-induced aggrecan breakdown was inhibited by TIMP-1 or by the N-terminal portion of TIMP-3, although FGF-2 did not affect production of the inhibitors TIMP-1 and TIMP-3 when IL-1alpha was present. FGF-2 did not prevent IL-1alpha suppression of proteoglycan synthesis and did not negate its ability to stimulate the production of IL-6, IL-8, and MMPs 1, 3, and 13. CONCLUSION: Our findings suggest that FGF-2 may play a chondroprotective role in human articular cartilage by controlling the expression and activity of the aggrecanases ADAMTS-4 and ADAMTS-5.

Original publication




Journal article


Arthritis rheum

Publication Date





3498 - 3509


ADAM Proteins, ADAMTS4 Protein, ADAMTS5 Protein, Blotting, Western, Cartilage, Articular, Cells, Cultured, Chondrocytes, Endopeptidases, Enzyme-Linked Immunosorbent Assay, Fibroblast Growth Factor 2, Glycosaminoglycans, Humans, Interleukin-1alpha, Interleukin-6, Interleukin-8, Matrix Metalloproteinase 1, Matrix Metalloproteinase 13, Matrix Metalloproteinase 3, Procollagen N-Endopeptidase, Proteoglycans, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sulfates, Sulfur Radioisotopes, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-3