The clinical problem with RA is not only chronic joint inflammation, but also moreover progressive destruction of cartilage and bone. IL-1 and TNF-α are considered the leading factors in RA that drive the enhanced production of cytokines, chemokines and degradative enzymes . The definition of IL-17 as a pro-inflammatory T-cell derived cytokine produced by RA synovium has lead to the hypothesis that such a cytokine could also be involved in joint destruction. We have accordingly analyzed the role of IL-17 in the inflammation and destruction patterns associated with RA.
IL-17 shares many properties with IL-1 and TNF-α. The three cytokines activate the common transcription factor NF-κB in a variety of cell types. They all stimulate stromal cells such as dermal and synovial fibroblasts, endothelial cells and epithelial cells to secrete IL-6, IL-8 and PGE2 [16,21,31]. Interactions between these three cytokines further amplify these effects. IL-17 induces IL-1 and TNF-α production by human macrophages . Monocyte activation, conversely, induces Th1 cell differentiation through IL-12 production, and IL-12 increases IL-17 production by T cells as shown with T-cell clones . More importantly, combination of IL-17 with IL-1 or TNF-α often leads to synergistic or additive effects, which further increase their biological effects. The present study demonstrates the potency of IL-17, often similar to that of IL-1, to induce inhibition of type I collagen synthesis by synovium and bone, but also of PG synthesis by cartilage. As Th1 cells infiltrate RA synovium, IL-17 produced by some of these Th1 cells can increase IL-1 and TNF-α production, enhancing the rate of degradation and lack of repair, which are characteristics of RA. Conversely, in osteoarthritis, where the contribution of T cells is less pronounced, destruction occurs but collagen synthesis is not as strongly inhibited. The presence of T cells, more precisely of Th1 cells, appears to be linked to defective repair when comparing the two conditions.
Inflammation and tissue destruction in RA synovium result from complex cell-cell interactions. Interactions between antigen presenting cells and CD4+ T cells lead to macrophage activation and secretion of IL-1 and TNF-α [2,34]. These factors stimulate matrix degradation collagen in synovium, cartilage and bone. Similar results were obtained with IL-17 on induction of matrix metalloproteinase-1 production by synoviocytes and collagenase activity by synovium . The present study extends these results by showing an enhanced effect when combined with IL-1.
Cartilage destruction is a major consequence of chronic synovitis. At an early stage, cytokines and other soluble factors acting on chondrocytes most probably induce such a process by diffusion. At a later stage, proliferation and activation of synovial cells lead to pannus formation that invades and destroys cartilage. Previous studies have demonstrated that cartilage degradation is largely dependent on IL-1 and TNF-α. We show in this paper that cartilage degradation can also be induced by IL-17 inhibiting PG synthesis and increasing its destruction. IL-17 has also already been shown to induce nitric oxide and stromelysin expression by isolated chondrocytes [36,37]. Administration of IL-17 into normal knee was, more importantly, able to induce such degradation . It is important to notice that such effect was observed using IL-17 alone and not in an inflamed joint where IL-1, TNF-α and IL-17 would have been already present. The endogenous secretion of IL-17 from cartilage appears unlikely and was not evaluated as IL-17 is still considered a T-cell specific cytokine.
The major contribution of this work is the demonstration of the role of IL-17 and thus of T cells from bone in destruction and defective formation. This was shown using specific IL-17 inhibitors. The important inhibition observed when blocking IL-17 alone can be explained by the synergistic interaction between IL-17 and other cytokines, as first shown with fibroblasts and synoviocytes [16,21]. Th2 cell cytokines such as IL-4 have conversely been shown to inhibit osteoclastogenesis. In a previous study using the same model, we showed that exogenous IL-4 was able to decrease bone destruction through an inhibitory effect on osteoclast survival . In keeping with the Th classification of cytokines, IL-17 appears to have the opposite effect in providing signals for osteoclast activity leading to increased bone destruction and reduced formation. This extends the results in the mouse showing a defective formation with IL-17 [19,20]. Previous studies have already demonstrated the direct contribution of T cells to osteoclast differentiation through cell contacts with osteoclasts . T cells were shown to express RankL in particular [6,40]. Furthermore, this activator of osteoclast formation and activation is also present in RA synovium [41,42]. Administration of IL-4 in the mouse model of collagen arthritis was able to control cartilage and bone destruction through an inhibition of the expression of IL-1, TNF-α, IL-17 and RankL .
Osteoclasts are specialized cells with the capacity of resorbing bone, whereas osteoblastic stromal cells are responsible for matrix formation. Bone formation is regulated by an event referred to as the coupling of formation to resorption, which is mediated in part by locally produced growth factors. Because of the intimate relationship between bone marrow cells and bone-specific cells, marrow cells and their products contribute to the bone microenvironment and influence the regulation of bone cell differentiation and activity. In the context of RA, early juxta-articular bone loss appears to result from in situ bone activation. Results with paired samples have shown a much higher level of destruction in bone compared with the synovium. It appears now that juxta-articular bone can produce bone-resorbing cytokine(s) from a subset of pro-inflammatory Th1 cells. These results obtained ex vivo in man extend those obtained in the mouse, which showed a direct effect of IL-17 on bone resorption .
The present data have significant implication for the therapeutic control of joint damage during inflammation. We could downregulate type I collagen degradation in both synovium and bone using specific IL-17 inhibitors. As IL-17 can increase IL-1 and TNF-α production by macrophages, blocking IL-17 will also decrease IL-1 and TNF-α actions. Furthermore, combining inhibitors of IL-17 with those of IL-1 and TNF-α may lead to a better effect. IL-17 may accordingly represent a target of interest for the treatment of RA, particularly to reduce its consequences on destruction.