ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 347

The Loss of S100A4 Prevents Induction of Experimental Arthritis in Human Tumour Necrosis Factor Transgenic Mouse Model

Michal Tomcik1, Christine Boehm2, Carina Scholtysek3, Lucie Andres Cerezo4, Wolfgang Baum3, Clara Dees3, Christian Beyer3, Jerome Avouac5, Pawel Zerr3, Katrin Palumbo-Zerr3, Alfiya Akhmetshina3, Radim Becvar1, Oliver Distler6, Mariam Grigorian7, Gerhard Kroenke3, Georg A. Schett8, Joerg HW Distler3 and Ladislav Senolt1, 1Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic, 2Division of Rheumatology, Medical University of Vienna, Vienna, Austria, 3Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 4Institute of Rheumatology, Department of Clinical and Experimental Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic, 5Paris Descartes University and INSERM U1016, Rheumatology A department, Cochin Hospital, Paris, France, 6Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland, 7Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark, 8Dept of Medicine 3, Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Rheumatoid Arthritis: Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: Our previous study demonstrated increased levels of S100A4 protein in sera, synovial fluid and synovial membrane of patients with rheumatoid arthritis (RA) compared to osteoarthritis. S100A4 regulates apoptosis and induces production of matrix metalloproteinases by synovial fibroblasts. Furthermore, S100A4 stimulates synthesis of tumour necrosis factor (TNF)-α by mononuclear cells and CD3 lymphocytes. The aim of this study was to investigate the effect of loss of S1004 in the induction of experimental arthritis in the human TNF transgenic (hTNFtg) mouse model.

Methods: We crossed the heterozygous hTNFtg mice with S100A4 knockout (S100A4-/-) mice. Following genotype determination, mice were clinically assessed for paw swelling, grip strength, leg movement and body weight every week from 6th to 14th week of age in a blinded manner. Sections of hind paws and tibias were histologically analyzed for synovial inflammation, cartilage loss, bone erosions, osteoclast numbers and bone formation parameters with the OsteoMeasure image analysis system.

Results: In the group of hTNFtg;S100A4-/- mice, paw swelling and grip strength were significantly improved compared to hTNFtg;S100A4+/+ (p<0.05 for both parameters). Although not significant, body weight of hTNFtg;S100A4-/- mice was slightly increased. Consistent with the clinical observations, histological analysis of the tarsal joints of hTNFtg;S100A4-/- mice showed reduced pannus formation (area of inflammation decreased by 66±3%, p<0.01) and cartilage destruction  (cartilage loss decreased by 63±6%, p<0.01) compared to hTNFtg;S100A4+/+ mice. Similarly, osteoclast numbers were decreased by 84±3%, (p<0.01) and bone erosions were less severe (area of bone erosion decreased by 81±4%, p<0.01) in hTNFtg;S100A4-/- mice. Furthermore, hTNFtg;S100A4-/- mice were protected from systemic bone loss. Absence of S100A4 completely reversed increased osteoclast formation and bone resorption in hTNFtg mice. hTNFtg; S100A4-/- mice had an increased bone volume per total volume (BV/TV) by 78±20% (p<0.05), as well as a decrease in trabecular separation by 39±4% (p<0.05) compared to hTNFtg;S100A4+/+. The protection from systemic bone loss observed in hTNFtg;S100A4-/-  mice was further supported by decreased numbers of osteoclasts per bone perimeter (N.Oc/B.Pm decreased by 43±2%, p<0.01), decreased bone surface covered by osteoclasts (Oc.S/BS decreased by 52±3%, p<0.01), increased numbers of osteoblasts per bone perimeter (N.Ob/B.Pm increased by 129±20%, p<0.05) and increased bone formation rate per bone surface (BFR/BS increased by 112±18%, p<0.05).

Conclusion: These results suggest that the loss of S100A4 effectively prevented the induction of experimental arthritis via protecting against TNF-induced synovial inflammation, cartilage and bone destruction, and systemic bone loss. Thus, S100A4 might represent a novel therapeutic target in RA.

Disclosure:

M. Tomcik,
None;

C. Boehm,
None;

C. Scholtysek,
None;

L. Andres Cerezo,
None;

W. Baum,
None;

C. Dees,
None;

C. Beyer,
None;

J. Avouac,
None;

P. Zerr,
None;

K. Palumbo-Zerr,
None;

A. Akhmetshina,
None;

R. Becvar,
None;

O. Distler,

Actelion, Pfizer, Boehringer-Ingelheim, Bayer, Roche, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec,

2,

Actelion, Pfizer, Boehringer-Ingelheim, Bayer, Roche, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec,

5,

Actelion, Pfizer and Ergonex,

8;

M. Grigorian,
None;

G. Kroenke,
None;

G. A. Schett,
None;

J. H. Distler,
None;

L. Senolt,
None.

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