**3. Mechanisms of exercise in rheumatoid arthritis treatment**

Although the beneficial effects of exercise for rheumatoid arthritis patients are well documented, the mechanisms are still largely unclear. As detailed previously, the effects of

Molecular Effects of Exercise in Rheumatoid Arthritis 319

other pro-inflammatory molecules (Chowdhury et al. 2003; Agarwal et al. 2004; Ferretti et al.

Exposure of meniscal or articular chondrocytes to proinflammatory cytokines (e.g. IL-1β and TNF-α) is reported to result in the expression of cyclo-oxygenase 2, inducible nitric oxide synthase, and genes involved in cartilage catabolism, such as matrix metalloproteinases 9 and 13 (Gassner et al. 1999). By contrast, when cells are subjected to mechanical stimuli in the form of cyclic tensile strain, they display a blunted response to cytokine exposure, thereby antagonizing the proinflammatory and catabolic effects of these cytokines (Ferretti et al. 2006; Madhavan et al. 2006). Interestingly, this anti-catabolic response seems to be mediated by inhibition of nuclear translocation of Nuclear factor-kappa B (NF-κB) and modulation of upstream signaling events associated with NF-κB, suggesting that mechanical activity can act at multiple points within the proinflammatory signaling network to counteract cytokine-induced proinflammatory gene expression (Dossumbekova et al. 2007). NF-*κ*B transcription factors regulate a wide range of pro-inflammatory and anti-apoptotic genes, and are involved in both acute and chronic inflammatory responses. NF-*κ*B is a rapid response, multiple-stimuli inducible transcription factor that is controlled by sequential signal activation cascades (Seguin and Bernier 2003). In the classical NF-*κ*B signaling pathway, binding of pro-inflammatory mediators, such as IL-1β, TNF-*α*, and/or LPS to their cognate receptors leads to activation of a series of receptor-associated signaling molecules leading to activated NF-*κ*B, which translocates to the nucleus, where it binds to the consensus sequences of several genes including pro-inflammatory cytokines and mediators (Ghosh and Karin 2002; Hoffmann et al. 2002; Liacini et al. 2003). Mechanical signals of low/physiological magnitudes block the IL-1β-induced transcriptional activity of NF-κB by intercepting multiple steps in the NF-κB signaling cascade. In chondrocytes, cyclic tensile strain of low magnitudes does not appear to inhibit IL-1β, TNF-α, or LPS receptor-mediated pro-inflammatory gene induction (Agarwal et al. 2004; Dossumbekova et al. 2007; Madhavan et al. 2007). These findings suggest that mechanical signals use specific target

Another transcriptional regulator which plays a critical role in cartilage homeostasis is CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2). CITED2 expression is increased by moderate flow shear (5 dyn/cm2), intermittent hydrostatic pressure (1-5 MPa), and joint motion (Yokota et al. 2003; Leong et al. 2011). The induction of CITED2 *in vivo* by joint motion loading was correlated with the downregulation of MMP-1 and the maintenance of cartilage matrix integrity (Leong et al. 2011), suggesting it plays a key role in mediating the anti-catabolic effects of moderate loading. The induction of CITED2 by physiologic loading was mediated by mitogen-activated protein kinase (MAPK) p38δ, and CITED2 regulated the transcription of MMPs (ie. MMP-1) by competing with MMP transactivator ETS-1 for binding to limiting amounts of co-activator p300 (Leong et al.

There is also evidence of crosstalk between the anti-inflammatory and anti-catabolic pathways. CITED2, induced by p38δ, has also been demonstrated to be upregulated in response to IL-4 (Sun et al. 1998), raising the possibility these two pathways could work in synergy. Furthermore, treatment strategies involving gene transfer of IL-4 or IL-10

**3.3 Crosstalk between anti-inflammatory and anti-catabolic responses** 

2005; Chowdhury et al. 2006; Deschner et al. 2006).

sites to trigger NF-κB signaling.

2011).

exercise are commonly characterized as anti-inflammatory and anti-catabolic. Each of these components is mediated by distinct signalling pathways and evidence indicates crosstalk between these pathways (see Figure 1 for hypothesized pathways/mechanisms).
