**2.3.2 Local effects on cartilage**

Clinical trials investigating the anti-inflammatory effect of exercise in the articular cartilage of RA patients are lacking, but results from clinical studies of osteoarthritis patients and animal models of RA suggest that moderate exercise has an anti-inflammatory effect on cartilage. Following acute resistance exercise, a significant increase in IL-10 was observed in the intra-articular and synovial spaces of subjects who exercised when compared to a nonexercise group (Helmark et al. 2010). Increases in IL-10 expression were also reported in chondrocytes in antigen-induced arthritis, an animal model of rheumatoid arthritis, after two weeks of continuous passive motion when compared to immobilized joints (Ferretti et al. 2005; Ferretti et al. 2006). Continuous passive motion also suppressed expression of IL-1β and inflammatory mediator COX-2 (Ferretti et al. 2006). Together, these data suggest that physiologic loading has the potential to generate anti-inflammatory biomechanical signals in cartilage, at least in part, by inducing IL-10.

To test the direct effect of IL-10 on rheumatic activity, collagen-induced arthritis mice were treated with recombinant IL-10, which resulted in a mild, but significant suppression of arthritic phenotype/symptoms (Johansson et al. 2001). Endogenous IL-10 plays a pivotal role in the regulation of antigen (streptococcal cell wall)-induced arthritis (Lubberts et al. 1998), since the blocking of endogenous IL-10 with anti-IL-10 antibodies resulted in a

play a metabolic, rather than an immunological role (Walsh et al. 2011). Following the increase of IL-6 in response to exercise in healthy individuals, IL-10 and IL-1 receptor antagonist (IL-1ra) are released into the circulation (Petersen and Pedersen 2006). Notably, an infusion of IL-6 enhanced plasma levels of IL-1ra and IL-10, (Steensberg et al. 2003). This suggests that the anti-inflammatory effect of exercise can be attributed, at least in part, to the induction of IL-6 and the creation of an anti-inflammatory environment (Table 2). Of note, no changes in serum IL-6 were detected in RA patients after exercise, but this might be attributable to a less strenuous exercise regimen when compared to healthy individuals (Knudsen et al. 2008). It is also possible that the anti-inflammatory effect of exercise is

blunted in patients with RA, but this requires further study.

Strength training (humans) Increase IL-15

Table 2. Anti-inflammatory and anti-catabolic effects of exercise

**2.3.2 Local effects on cartilage** 

in cartilage, at least in part, by inducing IL-10.

Type of exercise Beneficial effect on health

Aerobic exercise (humans) Increase plasma levels of IL-10, IL-1ra

Cycling (humans) Suppress endotoxin-induced TNF-α

Continuous passive motion (rabbits) Suppression of proteoglycan loss

Continuous passive motion (rats) Suppression of proteoglycan loss

Clinical trials investigating the anti-inflammatory effect of exercise in the articular cartilage of RA patients are lacking, but results from clinical studies of osteoarthritis patients and animal models of RA suggest that moderate exercise has an anti-inflammatory effect on cartilage. Following acute resistance exercise, a significant increase in IL-10 was observed in the intra-articular and synovial spaces of subjects who exercised when compared to a nonexercise group (Helmark et al. 2010). Increases in IL-10 expression were also reported in chondrocytes in antigen-induced arthritis, an animal model of rheumatoid arthritis, after two weeks of continuous passive motion when compared to immobilized joints (Ferretti et al. 2005; Ferretti et al. 2006). Continuous passive motion also suppressed expression of IL-1β and inflammatory mediator COX-2 (Ferretti et al. 2006). Together, these data suggest that physiologic loading has the potential to generate anti-inflammatory biomechanical signals

To test the direct effect of IL-10 on rheumatic activity, collagen-induced arthritis mice were treated with recombinant IL-10, which resulted in a mild, but significant suppression of arthritic phenotype/symptoms (Johansson et al. 2001). Endogenous IL-10 plays a pivotal role in the regulation of antigen (streptococcal cell wall)-induced arthritis (Lubberts et al. 1998), since the blocking of endogenous IL-10 with anti-IL-10 antibodies resulted in a

(Walsh et al. 2011)

(Starkie et al. 2003)

(Pedersen and Febbraio 2008)

Downregulation of MMP-1 Upregulation of IL-10

Downregulation of MMP-1, -3 (Leong et al. 2010; Leong et al. 2011)

(Ferretti et al. 2005; Ferretti et al. 2006)

sustained arthritis with denser synovial infiltrates as well as enhanced cartilage damage. Adding exogenous IL-10 further enlarged the suppressive effect of endogenous IL-10. However, these findings require further investigation in human clinical trials of RA patients.

## **2.4 Anti-catabolic effects of exercise on cartilage**

Considering cartilage destruction is a hallmark of RA, the role of exercise in maintaining cartilage matrix integrity is of great importance (Table 2) (Maini and Feldmann 2004). Articular cartilage functions as a nearly frictionless bearing surface while uniformly transferring loads on underlying bone and preventing high stress concentrations. Cartilage consists of one cell type, the chondrocyte, embedded in an extracellular matrix of mainly type II collagen and proteoglycans (Milner 2008). Physiologic loading of the cartilage tissue is required to maintain tissue homeostasis, while non-physiologic loading (disuse and overuse) promotes its degradation (Sun 2010). Intensive dynamic and weightbearing exercises were originally considered detrimental for patients with RA due to concerns of exacerbating disease, (van den Ende et al. 1996), but studies have shown such exercise does not cause an increase in the rate of damage to either large (de Jong et al. 2003) or small joints (de Jong et al. 2004). There were no significant differences in the rate of damage of large joints 18 months following the end of a high-intensity program between RA patients who discontinued exercise and those who were still exercising (de Jong et al. 2009). Furthermore, levels of cartilage oligomeric matrix protein (COMP), a measure of cartilage damage were unchanged after 3 months of exercise in RA patients, suggesting exercise did not cause significant damage to the cartilage matrix (de Jong et al. 2008). Exercise may also enhance joint lubrication, further acting to promote the health of the RA joint. During joint movement, synovial fluid is squeezed out from between the two surfaces of the joint, resulting in fluid film lubrication (Isenberg et al. 2004). Lubricin, a mucinous glycoprotein secreted by synovial fibroblasts, is the factor responsible for lubrication (Jay et al. 2001), and reduced levels of this protein found in RA patients may increase joint friction and promote cartilage degradation (Jay et al. 2004; Elsaid et al. 2007). However, whether exercise increases lubricin expression in patients with RA has not yet been determined. Exercise also promotes adequate strength of the muscles and surrounding joint soft tissues, providing optimal joint stability, alignment and attenuation of impact and compressive forces (Sun 2010).

After vigorous exercise in patients with moderate disease activity, a reduction in the number of diseased joints is observed (Minor et al. 1989; van den Ende et al. 1996). Animal studies have demonstrated physiologic loading of joints exerts beneficial effects by suppressing the activity of proteolytic enzymes in healthy and arthritic rats. Passive joint motion prevented cartilage destruction due to inactivity and downregulated MMPs 1 and 3 (Leong et al. 2010; Leong et al. 2011). In antigen-induced rabbits, passive motion prevented proteoglycan loss and suppressed expression of MMP-1 (Ferretti et al. 2005; Ferretti et al. 2006).
