Effects of FGF-2 and FGF receptor antagonists on MMP enzymes, aggrecan, and type II collagen in primary human OA chondrocytes.
OBJECTIVE
Fibroblast growth factor (FGF)-2 is a member of the FGF family and is found in the synovial fluid of patients with osteoarthritis (OA). The aim of this study was to investigate the effects of FGF-2 on human OA cartilage/chondrocytes by examining the association between FGF-2 and the cartilage degrading enzymes matrix metalloproteinase (MMP)-1 and MMP-13 and the major cartilage matrix components aggrecan and collagen II.


METHODS
Cartilage samples were obtained from 97 OA patients undergoing total knee replacement surgery. Cartilage tissue cultures were conducted and levels of FGF-2, MMP-1, and MMP-13 released into the culture medium were measured by immunoassay. The effects of FGF-2 on the expression of MMP-1, MMP-13, aggrecan, and collagen II were further investigated in cultures of primary human OA chondrocytes.


RESULTS
FGF-2, MMP-1, and MMP-13 were released into the culture medium from cartilage samples obtained from patients with OA. 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). FGF-2 also 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. Furthermore, FGF receptor antagonists AZD4547 and NVP-BGJ398 down-regulated the expression of MMP-1 and MMP-13 and up-regulated aggrecan and collagen II both in the absence and in the presence of exogenous FGF-2.


CONCLUSIONS
Our results suggest that, in contrast to its growth factor-like effects in some other tissues, FGF-2 induces catabolic effects in human OA cartilage. Moreover, FGF receptor antagonists showed promising beneficial effects on the balance of catabolic and anabolic factors within OA cartilage.
The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , Tampere , Finland.
E
E
Nummenmaa
M
M
Hämäläinen
T
T
Moilanen
K
K
Vuolteenaho
E
E
Moilanen
D000368:Aged; D053674:Aggrecans / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008660:Metabolism / Q000187:drug effects; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*
C572463:AZD4547; D053674:Aggrecans; D001549:Benzamides; D024043:Collagen Type II; D010671:Phenylurea Compounds; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; C568950:infigratinib; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1