RHEUMATOLOGY RESEARCH LABORATORY NIJMEGEN NCMLS
Program: Mechanisms and modulation of chronic inflammation and joint tissue destruction during Rheumatoid Arthritis.

Peter L.E.M. van Lent

Program leader

Email: [email protected]

Research program

Among rheumatic diseases more than hundred different joint disorders are distinguished. Rheumatoid arthritis (RA) manifests itself as one of the most severe and most frequently occurring form. RA is characterised by chronic inflammations and tissue destruction in joints. Our main goal is to investigate mechanisms involved in chronic inflammation and joint tissue destruction and to develop new therapies for treating this disease. This is done both in experimental models of arthritis as in the human disease. In recent years we investigated the role of monocytes/macrophages and their products in regulating joint inflammation and cartilage destruction. Macrophages are present in the lining layer covering the synovium.Furthermore, during arthritis large amounts of monocytes/ macrophages migrate from the blood into joint and after activation release more than hundred mediators. Many of these factors are involved in regulating joint inflammation and cartilage destruction.

Many triggers activate macrophages. IgG containing immune complexes are potent activators of macrophages and communicate with macrophages via Fc receptors. Activation of macrophages by ICs leads to release of cytokines (interleukin-1 and tumor necrosis factor) and enzymes mediating joint destruction.

The areas of emphasis include:

Mechanistic:

a) The role of enzymes in joint destruction during experimental arthritis

b) The role of monocytes/macrophages and their products in inflammation and cartilage destruction during experimental and human arthritis.

Therapeutical:

c) Development of new therapies by targeting macrophages or their products.

The goals of this group are:

-To understand which enzymes (particularly metalloproteinases and serine proteinases) are responsible for joint destruction.

-To further elicidate the central role of macrophages and their products in joint inflammation and destruction during experimental arthritis.

-To investigate which Fc Receptors are important in cartilage destruction during arthritis.

-To develop new therapies by 1) selective removal of macrophages 2) modulating macrophage functions by Fc receptors 3) neutralising macrophage products like cytokines.

 

 

Participating Researchers:

Pilar Barrera-Rico- Rheumatologist- Therapeutic trials in patients with rheumatoid arthritis.

Arjen Blom-biologist PhD student- Role of macrophages in inflammation and joint destruction during experimental arthritis.

Karin Nabbe- biologist PhD student-Modulation of arthritis and cartilage destruction by Fc receptors. Dutch League against Rheumatism NR 99-1-402.

Nosomi Takahashi- PhD-Mechanisms of articular cartilage destruction.

 

Selected publications:

  1. Joyce BJ van Meurs, Peter LEM van Lent, Irwin I Singer, Ellen K Bayne, Fons van de Loo and Wim van den Berg. Interleukin-1 receptor antagonist prevents expression of the metalloproteinase-generated neoepitope VDIPEN during antigen-induced arthritis. Arthritis and Rheumatism 41:647-656,1998.
  2. Joyce BJ van Meurs, Peter LEM van Lent, Astrid EM Holthuysen, Irwin I. Singer, Ellen K. Bayne and WB van den Berg: Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis. Arthritis and Rheumatism 42(6):1128-1139,1999.
  3. Joyce van Meurs, PLEM van Lent, Reinout Stoop, Astrid Holthuysen, Irwin Singer, Ellen bayne, John Mudgett, Robin Poole, Clark Billinghurst, Peter van der Kraan, Pieter Buma and Wim van den Berg: Cleavage of aggrecan at the Asn341-Phe342 site coincides with the initiation of collagen damage in murine antigen-induced arthritis. Arthritis and Rheumatism in press.
  4. Joyce van Meurs, Peter van Lent, Astrid Holthuysen, Dimitri Lambrou, Ellen Bayne, Irwin Singer and WB van den Berg: Active matrix metalloproteinases are present in cartilage during immune complex-mediated arthritis: a pivotal role for stromelysin-1 in cartilage destruction. J of Immunology in press.
  5. Peter LEM van Lent, AJ van Vuuren, AB Blom, AEM Holthuysen, LBA van de Putte, JGJ van de Winkel and WB van den Berg: Role of FcR K chain in inflammation and cartilage damage during experimental antigen-induced arthritis: Arthritis and Rheumatism in press.


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