Rheumatoid Arthritis Linked to Blood Clotting Protein Fibrin

Fibrin, a protein involved in blood clotting, also has a prominent role in inflammatory response and development of rheumatoid arthritis, according to researchers at Cincinnati Childrens Hospital.

The study, published in the Nov. 2007 issue of the Journal of Clinical Investigation(1), suggests that therapies designed to interrupt the localized interaction of inflammatory cells and fibrin may help arthritis patients.

“Our study establishes that fibrin is a powerful, although context-dependent, determinant of inflammatory joint disease,” said Jay Degen, Ph.D., a researcher in Developmental Biology at Cincinnati Childrens and the studys lead author. “These findings also suggest that pharmacologically interrupting the interaction of fibrin and aMB2 might be efficacious in the treatment of arthritic disease as well as many other inflammatory diseases, such as multiple sclerosis.”

Blood Fibrin

Fibrin is a fibrous protein that bonds together to form a “mesh” which makes a hemostatic plug or clot, in conjunction with platelets, over a wound site. Fibrin is made from its fibrinogen, a blood glycoprotein synthesised in the liver.

It is established that fibrin deposits are a prominent feature of arthritic joints(2-4) and the protein appears to be a link between systems that control inflammation and bleeding within joints. Dr. Degen and his colleagues explained that in arthritic joints, the mesh-like matrices formed by fibrin to create blood clots may control local activity of inflammatory cells as well as support inappropriate tissue reorganization. Not only that, but, fibrin is a key constituent of particulates within joint synovial fluid(5).

Methods

The study used fibrinogen-deficient mice and mice with genetically mutant forms of fibrinogen retaining the clotting function but lacking platelet integrin receptor binding. Along with a third group of control mice, they were given injections of bovine type II collagen to provoke Collagen Induced Arthritis (CIA) of the knee and paw, a standard model for laboratory arthritis study(6).

Evaluation for arthritis was done using an arthritic index visual scoring system ranging from 0 to 4. 0 represented no detectable arthritis; 1, swelling and/or redness of paw or 1 digit; 2, 2 joints involved; 3, 3 joints involved; 4, severe arthritis of the entire paw and digits. The mice were also evaluated based on the degree of paw swelling using an arthritic severity score. Finally, mice were sacrificed at specified time periods for joint histological, mRNA, or enzyme analysis.

Rheumatoid Arthritis

Rheumatoid arthritis, affecting 2.1 million people in the United States alone, is a painful and debilitating disease involving chronic inflammation, tissue degeneration, loss of cartilage and bone and ultimately loss of joint mobility and function. While the diseases exact cause is not fully known, activation of specific components in the bodys immune system seem to play a major role in its onset and early progression.

The study shows that fibrin can influence inflammatory joint disease even in the absence of any trauma to joints. It also fits into currently emerging concepts in arthritis research which propose that leukocyte engagement of fibrin in tissue promotes arthritic disease, at least partly, by regulation of inflammatory cell function, including local cytokine production.

References

1. Matthew J. Flick, Christine M. LaJeunesse,, Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin Mß2 binding motif J. Clin. Invest. 117:32243235 (2007). doi:10.1172/JCI30134 Full Text

2. Wooley P.H., Dutcher J., Widmer M.B., Gillis S. 1993. Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice. J. Immunol. 151:66026607

3. Altieri D.C., Mannucci P.M., Capitanio A.M. 1986. Binding of fibrinogen to human monocytes. J. Clin. Invest. 78:968976 Abstract

4. Flick M.J., et al. 2004. Leukocyte engagement of fibrin(ogen) via the integrin receptor MÃ2/Mac-1 is critical for host inflammatory response in vivo. J. Clin. Invest. 113:15961606doi: 10.1172/JCI200420741 Full Text

5. Zacharski L.R., et al. 1992. Pathways of coagulation activation in situ in rheumatoid synovial tissue. Clin. Immunol. Immunopathol. 63:155162. Abstract

6. BASIC PROTOCOL 1: INDUCTION OF COLLAGEN-INDUCED ARTHRITIS IN THE MOUSE University of Tennessee Health Science Center

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