A8.14 The Anti-Proliferative Function of RSK2 in Synovial Fibroblasts Protects Against TNF-α-Induced Joint Destruction in Inflammatory Arthritis
Authors: Anja Derer, Christina Böhm, Bettina Herbort, Sybille Böhm, Kirsten Neubert, Michael Stock, Christine Zech, Georg Schett, Axel J Hueber, Jean-Pierre David
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background/Objectives</h3> 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 joints of arthritis patients as well as in the inflamed joints of mice overexpressing the human TNF-α (<i>hTNF</i>tg). These observations prompted us to investigate the function of RSK2 in the development of TNF-α-induced inflammatory arthritis. <h3>Materials and Methods</h3> <i>hTNF</i>tg mice were crossed with RSK2-deficient (<i>Rsk2<sup>y/-</sup></i>) mice. Clinical scoring and histomorphometry of the joints were assessed. We compared the levels of circulating pro-inflammatory cytokines as well as the cellularity of myeloid lineages in the spleen. The expression of cytokines and mesenchymal markers in the joints was determined via QPCR. Bone marrow transfer of <i>Rsk2<sup>y/-</sup></i> and wild-type littermates into <i>hTNF</i>tg mice was performed and clinical scoring as well as histomorphometry of the joints was assessed. Primary fibroblast-like synoviocytes (FLS) from <i>hTNF</i>tg and <i>hTNF</i>tg; <i>Rsk2<sup>y/</sup></i> mice were isolated to analyse their expression of inflammatory cytokines and metalloproteinases as well as their proliferation and apoptosis in vitro. <h3>Results</h3> RSK2 deficiency in <i>hTNF</i>tg 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 <i>hTNF</i>tg mice lacking RSK2. Increased activation of synovial fibroblasts and macrophages in the joints of <i>hTNF</i>tg<i>; Rsk2 <sup>y/-</sup></i> 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 <i>Rsk2 <sup>y/-</sup></i> bone marrow into <i>hTNF</i>tg 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 <i>hTNF</i>tg<i>; Rsk2 <sup>y/-</sup></i>, these cells displayed an increased proliferation rate. <h3>Conclusions</h3> 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.