Effects of Chemokines in Rheumatoid Arthritis Beyond Cell Recruitment

It seems obvious to assume that by virtue of their powerful regulatory effects of leukocyte recruitment, many chemokine/chemokine receptors may play an important role in an inflammatory disease of the joints such as RA. However, chemokines may have other effects in disease pathogenesis that may not be related to leukocyte chemotaxis.

10.6.1. Chemokines and Osteoclastogenesis

Localized bone reabsorption is one of the more characteristic features of RA. This osteopenia is mediated in part by increased accumulation of osteoclasts. Interestingly, a handful of chemokines have been shown to have a profound effect on osteoclast differentiation, although it is unknown whether chemokines are mediators of osteoclastogenesis and bone loss in arthritis. The osteoclasto-genic properties of the chemokine CCL3 have been extensively studied. CCL3 is present in inflamed joints in RA and experimental arthritis. Injection of recombinant CCL3 in vivo promotes a striking increase in osteoclast differentiation (96). Moreover, in the context of multiple myeloma, a disease in which just like RA, there is significant degree of localized bone reabsorption, CCL3 has been shown to promote osteoclastogenesis (97). CCL3 promotes osteoclast differentiation via CCR1 and CCR5 (98), and its effects are not fully dependent on the actions of the master osteoclast differentiation factor RANKL (99). Notably, chemokines such as CCL2 and CCL5 may also have a synergistic action on the ability of RANKL to promote osteoclast differentiation (100,101).

10.6.2. Chemokines and the Cartilage

A pathologic feature of the RA joints is the evidence of significant destruction of cartilage (102). Notably, chondrocytes themselves produce chemokines such as CXCL8, CXCL1, CCL2, CCL3, and CCL5 (103), and their production of CXCL8, CXCL1, CCL3, and CCL4 is increased in RA (104). Thus, it is likely that there is a role for chemokines and their receptors in cartilage degradation. Indeed, chemokines can induce the release of matrix-degrading enzymes such as matrix metalloproteinases 1, 3, and 13 and W-acetyl-beta-D-glucosaminidase. Furthermore, CXCL1 acting on CXCR2 can activate an apoptotic pathway in chondrocytes that leads to cell death (105).

10.6.3. Chemokines and Angiogenesis

Endothelial cells are likely to be important in the pathogenesis of RA. Activation of endothelial cells during inflammatory conditions is associated with upregulation of adhesion molecules and chemokines that would promote leukocyte migration from the blood into the joint tissue (106). Moreover, the RA synovium is rich in newly formed vessels as a consequence of increased angiogenesis. Different chemokines have angiogenic and angiostatic properties, and their levels in the joints may determine in part the magnitude of new blood vessel formation. For instance, CXCL8, CXCL5, CXCL1, and CTAP-III, che-mokines that contain the ELR (glutamyl-leucyl-arginyl) amino acid sequence, are potent angiogenic factors. In contrast CXCL4, CXCL9, and CXCL10, chemokines that lack the ELR motif, inhibit neovascularization (107). As an exception, the ELR-lacking CXCL12 is angiogenic potentially via its ability to influence migration and proliferation of endothelia progenitor cells (107). Interestingly, it has been shown that synoviocyte-derived CXCL12 accumulates, and it is immobilized on heparan sulfate molecules of endothelial cells, where it can promote angiogenesis and inflammatory cell infiltration, supporting a multifaceted function for this chemokine in the pathogenesis of rheumatoid arthritis (108).

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