Early structural changes in cartilage and bone are required for the attachment and invasion of inflamed synovial tissue during destructive inflammatory arthritis
- Adelheid Korb-Pap*,1,2,
- Athanasios Stratis*,3,
- Katja Mühlenberg3,
- Birgit Niederreiter1,
- Silvia Hayer1,
- Frank Echtermeyer4,
- Richard Stange3,
- Jochen Zwerina5,
- Thomas Pap3,
- Hermann Pavenstädt2,
- Georg Schett6,
- Josef S Smolen1,
- Kurt Redlich1
- 1Division of Rheumatology, Medical University Vienna, Vienna, Austria
- 2Department of Internal Medicine D, Nephrology and Rheumatology, University Hospital Munster, Muenster, Germany
- 3Institute of Experimental Musculoskeletal Medicine, University Hospital Munster, Muenster, Germany
- 4Department of Experimental Anaesthesia, University Hospital Hanover, Hanover, Germany
- 54th Medical Department, Hanusch Hospital, Vienna, Austria
- 6Department of Internal Medicine 3, University of Erlangen, Erlangen, Germany
- Correspondence to Kurt Redlich, Division of Rheumatology, Department of Internal Medicine III, Medical University Vienna, Währinger Guertel 18-20, A-1090 Austria;
- Received 30 June 2011
- Accepted 4 December 2011
- Published Online First 18 January 2012
Objective To elucidate the mechanisms involved in cartilage damage in an experimental model of rheumatoid arthritis (RA) by specifically addressing the time course of extracellular matrix degradation and the contribution of cell–matrix interactions for initiation and perpetuation of this process.
Methods The human tumour necrosis factor (TNF) transgenic (hTNFtg) mouse model of RA was used to analyse the time course of pannus attachment to the cartilage and cartilage destruction, respectively, and crossed hTNFtg mice with interleukin (IL)-1−/− animals were used to investigate the role of IL-1 on these TNF-induced mechanisms in vivo. In addition, an in vitro attachment assay using synovial fibroblasts (SFs) from hTNFtg mice and freshly isolated articular cartilage was used to determine the role of proteoglycan loss in attachment of SFs and the role of the transmembrane heparan sulfate proteoglycan syndecan-4.
Results In vivo analyses of hTNFtg mice showed that proteoglycan loss induced by IL-1 precedes and constitutes an important prerequisite for these processes as, in hTNFtg mice, IL-1 deficiency protected from the loss of cartilage proteoglycans and almost completely prevented the attachment and subsequent invasion of inflamed synovial tissue into cartilage. In vitro studies confirmed that loss of cartilage proteoglycans is required for attachment of SFs and that syndecan-4 is prominently involved in SF attachment and activation.
Conclusions The results of this study suggest that the loss of cartilage proteoglycans is an early event in the course of destructive arthritis that facilitates the attachment of the inflamed synovial membrane and also initiates matrix degradation and inflammation through cell–matrix interactions.
↵* AK-P and AS contributed equally to this work.
Funding This project was supported by Coordination Theme 1 (Health) of the European Community's FP7, grant agreement number HEALTH-F2-2008-223404 (MASTERSWITCH) and the Deutsche Forschungsgemeinschaft (DFG), grant number Pa689/7-1 and Pa689/7-2.
Competing interests None.
Ethics approval All animal procedures were approved by the local ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.