Galectin 3 and its binding protein in rheumatoid arthritis.
OBJECTIVE
To characterize the expression pattern and role of galectin 3 and galectin 3 binding protein (G3BP) in rheumatoid arthritis (RA), in comparison with galectin 1, and to explore whether soluble galectin 3 and G3BP, investigated in serum, synovial fluid, or cell culture supernatant, are associated with disease.


METHODS
Synovial tissues from patients with RA or osteoarthritis (OA), as well as from healthy controls, were analyzed for galectins 1 and 3 and G3BP by in situ hybridization and immunohistochemistry. Levels of galectin 3 and G3BP in serum and synovial fluid from patients with RA and OA and controls, as well as in cell culture supernatants, were determined by enzyme-linked immunosorbent assay (ELISA). In vitro, the intracellular expression of galectin 3 in RA and OA synovial fibroblasts after modulation with tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and anti-CD40 monoclonal antibodies was measured by flow cytometry.


RESULTS
In RA, galectin 3 messenger RNA and protein stained throughout the synovial membrane, whereas G3BP was particularly expressed at sites of bone destruction. In contrast, the expression of galectin 1 was not uniform in different RA specimens, and was never found at sites of invasion. In OA and normal synovial tissues, only a small number of cells were positive for galectins and/or G3BP. Galectin 3 was elevated in RA sera and synovial fluids, whereas G3BP was increased in RA synovial fluids only. In RA, serum galectin 3 correlated with C-reactive protein levels, whereas G3BP was associated with joint destruction and/or synovial cell activation as measured by the levels of cartilage oligomeric matrix protein. In vitro, RA synovial fibroblasts showed an increased release of galectin 3 into culture medium, as measured by ELISA, but decreased secretion of G3BP. In RA synovial fibroblasts with low basal expression of galectin 3, TNFalpha increased its intracellular level in a dose-dependent manner. In contrast, IL-1beta or anti-CD40 monoclonal antibodies showed no effect.


CONCLUSIONS
Our data indicate that galectin 3 and G3BP are not only involved in inflammation, but also contribute to the activation of synovial fibroblasts. The intracellular accumulation of galectin 3 can be enhanced by TNFalpha. Thus, galectin 3 and G3BP represent novel markers of disease activity in RA.
Ohshima
Shiro
S
Center of Experimental Rheumatology, University Hospital, Zurich, Switzerland.
Kuchen
Stefan
S
Seemayer
Christian A
CA
Kyburz
Diego
D
Hirt
Astrid
A
Klinzing
Stephanie
S
Michel
Beat A
BA
Gay
Renate E
RE
Liu
Fu-Tong
FT
Gay
Steffen
S
Neidhart
Michel
M
D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D015415:Biomarkers; D002097:C-Reactive Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000097:blood* / Q000235:genetics*; D064236:Cartilage Oligomeric Matrix Protein; D002448:Cell Adhesion / Q000276:immunology; D004265:DNA Helicases; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D037502:Galectin 3 / Q000097:blood* / Q000235:genetics*; D015870:Gene Expression; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D064235:Matrilin Proteins; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D000075223:Poly-ADP-Ribose Binding Proteins; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D012333:RNA, Messenger / Q000032:analysis; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology
D015415:Biomarkers; D002352:Carrier Proteins; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D037502:Galectin 3; D006023:Glycoproteins; D007375:Interleukin-1; D064235:Matrilin Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D012333:RNA, Messenger; C577553:TSP5 protein, human; D002097:C-Reactive Protein; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases