Activin A is an anticatabolic autocrine cytokine in articular cartilage whose production is controlled by fibroblast growth factor 2 and NF-kappaB.
OBJECTIVE
Proteomic analysis has previously shown that activin A, a member of the transforming growth factor beta family, is produced by human articular cartilage. This study was undertaken to investigate whether activin A affects cartilage matrix catabolism and how its production is regulated.


METHODS
The effect of exogenous activin A on interleukin-1-induced aggrecanase-generated neoepitope production was assessed by Western blotting, using medium from human cartilage explants. Levels of activin A production were determined by enzyme-linked immunosorbent assay. For genes of interest, messenger RNA (mRNA) induction in cartilage explants or primary chondrocyte monolayers was assessed by reverse transcriptase-polymerase chain reaction. Activin A activity in cartilage explant medium was measured by incubating it with human dermal fibroblasts and determining the increase in phospho-Smad2 by Western blotting.


RESULTS
Activin A (1-10 ng/ml) suppressed aggrecanase-mediated cleavage of aggrecan in human articular cartilage. Activin A mRNA and protein secretion were induced by dissection and culture of human or porcine articular cartilage. This activin A was biologically active. Its production was due to an active cellular process and was enhanced in osteoarthritic (OA) tissue. Activin A production on dissection was reduced by 80% by the fibroblast growth factor (FGF) receptor inhibitor PD173074 and by 70% by the IKK inhibitor BMS345541.


CONCLUSIONS
Activin A is potentially an anticatabolic molecule in articular cartilage. Its expression is induced by wounding in an FGF-2- and NF-kappaB-dependent manner. OA cartilage produced more activin A than did normal cartilage in vitro.
Alexander
Susan
S
Kennedy Institute of Rheumatology, Imperial College London, London, UK.
Watt
Fiona
F
Sawaji
Yasunobu
Y
Hermansson
Monika
M
Saklatvala
Jeremy
J
D028341:Activins / Q000378:metabolism* / Q000494:pharmacology; D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051899:Smad2 Protein / Q000378:metabolism; D034421:Sus scrofa
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D053674:Aggrecans; D016207:Cytokines; D007093:Imidazoles; D016328:NF-kappa B; C115711:PD 173074; D011743:Pyrimidines; D011810:Quinoxalines; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C422405:activin A; D016222:Fibroblast Growth Factor 2; D028341:Activins; D010450:Endopeptidases; C083641:aggrecanase