Background/Purpose: The fibroblast growth factor (FGF) family represents an interesting group of molecules which are involved in the regulation of connective tissue development and metabolism. FGF-18 has promising effects also in articular cartilage whereas FGF-2 seems to signal through different cellular receptors and its role in osteoarthritis (OA) remains unknown in many aspects. In the present study we investigated the presence and effects of FGF-2 in OA joints by assessing the associations of FGF-2 with cartilage degrading matrix metalloproteinase (MMP) enzymes and with the synthesis of the major cartilage matrix components aggrecan and collagen as well as by investigating the effects of FGF receptor antagonists.

Methods: Synovial fluid and cartilage samples were obtained from 97 OA patients undergoing total knee replacement surgery (60 females and 37 males, BMI 30.9 ± 0.6 kg/m², age 69.8 ± 1.0 years; mean ± SEM). FGF-2 concentrations in the synovial fluid and cartilage culture medium were measured by immunoassay. The effects of FGF-2 and its receptor antagonists on the production of MMP-1, MMP-13, aggrecan and collagen II were investigated in cultures of primary human OA chondrocytes. The study was approved by the Ethics Committee of Tampere University Hospital, Tampere, Finland and it was carried out in accordance with the Declaration of Helsinki. The patients gave their written informed consent, and their diagnosis was confirmed to fulfill the ACR classification criteria for osteoarthritis.

Results: FGF-2 was present in OA synovial fluid and released into the culture media from cartilage samples obtained from OA patients. Interestingly, FGF-2 concentrations correlated positively with the concentrations of MMP-1 (r = 0.414, p < 0.001) and MMP-13 (r = 0.362, p < 0.001) (Fig. 1) in the cultures of OA cartilage. Further, FGF-2 up-regulated the production of MMP-1 and MMP-13, and down-regulated the expression of aggrecan and collagen II, in human OA chondrocyte cultures. More importantly, FGF receptor antagonists AZD4547 and NVP-BGJ398 (10-300nM) down-regulated the production of MMP-1 and MMP-13 and up-regulated the expression of aggrecan and collagen II in a concentration dependent manner, and not only in the presence but also in the absence of exogenous FGF-2.  

Conclusion: The present results suggest that, in contrast to its growth factor like effects in some other conditions, FGF-2 induces catabolic and anti-anabolic effects in osteoarthritis. Moreover, FGF-receptor antagonists showed promising beneficial effects on the balance of catabolic and anabolic mediators within OA cartilage.