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Abstract Number: 2227

The Anti-Proliferative Function of RSK2 in Synovial Fibroblasts Protects Against TNF-á-Induced Joint Destruction in Inflammatory Arthritis

Anja Derer1, Christina Boehm1, Bettina Groetsch1, Michael Stock1, Kirsten Neubert2, Sybille Boehm3, Bettina Sehnert1, Georg Schett1, Axel J. Hueber4 and Jean-Pierre David5, 1Dept of Medicine 3, Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 2Clinical Research Group, Nikolaus-Fiebiger Center, University of Erlangen-Nuremberg, Erlangen, Germany, 3Institute of Genetics, Department of Biology, University of Erlangen-Nuremberg, Erlangen, Germany, 4Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany, 5Group Genes and Transcription, Institute of Osteology and Biomechanics (IOBM), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, signal transduction and tumor necrosis factor (TNF)

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Session Information

Title: Rheumatoid Arthritis - Animal Models II

Session Type: Abstract Submissions (ACR)

Background/Purpose: The pro-inflammatory cytokine Tumor Necrosis Factor alpha (TNF-α) directly activates the ribosomal S6 kinase RSK2 in vitro. We recently demonstrated the protective effect of RSK2 against TNF-induced bone loss. Interestingly, we found an increased activation of RSK2 in the inlfamed joints of arthritis patients as well as mice overexpressing the human TNF-α (hTNFtg). This prompted us to investigate the function of RSK2 in the development of TNF-α-induced inflammatory arthritis.

Methods: hTNFtg mice were crossed with RSK2-deficient (Rsk2y/-) mice. Clinical scoring and histomorphometry of the joints were assessed. Levels of circulating pro-inflammatory cytokines as well as the cellularity of myeloid lineages in the spleen were compared. The expression of cytokines and mesenchymal markers in the joints was determined via QPCR. Bone marrow transfer of Rsk2y/- and wild-type littermates into hTNFtg mice was performed and clinical scoring as well as histomorphometry of the joints was assessed. Primary fibroblast-like synoviocytes (FLS) from hTNFtg and hTNFtg;Rsk2y/ mice were isolated to analyze their expression of inflammatory cytokines and metalloproteinases as well as their proliferation and apoptosis in vitro.

Results: RSK2 deficiency in hTNFtg mice resulted in an early onset of clinical signs of arthritis as well as a drastic exacerbation of inflammation, increased cartilage destruction and increased local bone destruction. Increased levels of circulating pro-inflammatory cytokines and the increased proportion of all myeloid lineages in the spleen confirmed the enhanced inflammation in the hTNFtg mice lacking RSK2. Increased activation of synovial fibroblasts and macrophages in the joints of hTNFtg;Rsk2y/- mice was demonstrated by the locally increased expression of pro-inflammatory cytokines and matrix metalloproteinases (MMPs). Importantly, the phenotype could not be transmitted by the transfer of Rsk2y/- bone marrow into hTNFtg mice that demonstrated the essential role for RSK2 expression in mesenchymal cells driving the pathogenesis. In agreement, although no difference in the expression of pro-inflammatory cytokines or MMPs nor a change in apoptosis was detected in synovial fibroblasts isolated from hTNFtg;Rsk2y/-, these cells displayed an increased proliferation rate.

Conclusion: The anti-proliferative function of RSK2 controls a cell autonomous negative feed-back against the activation of synovial fibroblasts by TNF-α, therefore limiting joint destruction in arthritis. Thus, activation of RSK2 is a potential target for the treatment of both local and systemic bone destruction in RA.


Disclosure:

A. Derer,
None;

C. Boehm,
None;

B. Groetsch,
None;

M. Stock,
None;

K. Neubert,
None;

S. Boehm,
None;

B. Sehnert,
None;

G. Schett,
None;

A. J. Hueber,
None;

J. P. David,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-anti-proliferative-function-of-rsk2-in-synovial-fibroblasts-protects-against-tnf-a-induced-joint-destruction-in-inflammatory-arthritis/

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