Trefoil factor 3 is induced during degenerative and inflammatory joint disease, activates matrix metalloproteinases, and enhances apoptosis of articular cartilage chondrocytes.
OBJECTIVE
Trefoil factor 3 (TFF3, also known as intestinal trefoil factor) is a member of a family of protease-resistant peptides containing a highly conserved motif with 6 cysteine residues. Recent studies have shown that TFF3 is expressed in injured cornea, where it plays a role in corneal wound healing, but not in healthy cornea. Since cartilage and cornea have similar matrix properties, we undertook the present study to investigate whether TFF3 could induce anabolic functions in diseased articular cartilage.


METHODS
We used reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemistry to measure the expression of TFF3 in healthy articular cartilage, osteoarthritis (OA)-affected articular cartilage, and septic arthritis-affected articular cartilage and to assess the effects of cytokines, bacterial products, and bacterial supernatants on TFF3 production. The effects of TFF3 on matrix metalloproteinase (MMP) production were measured by enzyme-linked immunosorbent assay, and effects on chondrocyte apoptosis were studied by caspase assay and annexin V assay.


RESULTS
Trefoil factors were not expressed in healthy human articular cartilage, but expression of TFF3 was highly up-regulated in the cartilage of patients with OA. These findings were confirmed in animal models of OA and septic arthritis, as well as in tumor necrosis factor alpha- and interleukin-1beta-treated primary human articular chondrocytes, revealing induction of Tff3/TFF3 under inflammatory conditions. Application of the recombinant TFF3 protein to cultured chondrocytes resulted in increased production of cartilage-degrading MMPs and increased chondrocyte apoptosis.


CONCLUSIONS
In this study using articular cartilage as a model, we demonstrated that TFF3 supports catabolic functions in diseased articular cartilage. These findings widen our knowledge of the functional spectrum of TFF peptides and demonstrate that TFF3 is a multifunctional trefoil factor with the ability to link inflammation with tissue remodeling processes in articular cartilage. Moreover, our data suggest that TFF3 is a factor in the pathogenesis of OA and septic arthritis.
Rösler
Sophie
S
Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany.
Haase
Tobias
T
Claassen
Horst
H
Schulze
Ute
U
Schicht
Martin
M
Riemann
Dagmar
D
Brandt
Jörg
J
Wohlrab
David
D
Müller-Hilke
Brigitte
B
Goldring
Mary B
MB
Sel
Saadettin
S
Varoga
Deike
D
Garreis
Fabian
F
Paulsen
Friedrich P
FP
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001170:Arthritis, Infectious / Q000378:metabolism; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000166:cytology*; D002460:Cell Line; D019902:Chondrocytes / Q000502:physiology*; D018076:DNA, Complementary / Q000096:biosynthesis; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007592:Joint Diseases / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D051379:Mice; D010003:Osteoarthritis / Q000378:metabolism; D010455:Peptides / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071165:Trefoil Factor-3; D015854:Up-Regulation
D018076:DNA, Complementary; D010455:Peptides; D011994:Recombinant Proteins; C082495:TFF3 protein, human; D000071165:Trefoil Factor-3; D020782:Matrix Metalloproteinases