Fibroblast growth factor 2 inhibits induction of aggrecanase activity in human articular cartilage

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‐1α (IL‐1α) 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 35 S‐sulfate incorporation. Results IL‐1α 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 α and retinoic acid also stimulated release of neoepitope, and this was also suppressed by FGF‐2. IL‐1α induced ADAMTS‐4 and ADAMTS‐5 mRNA in primary human chondrocytes, and this was inhibited by FGF‐2. IL‐1α–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‐1α was present. FGF‐2 did not prevent IL‐1α 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.