Stimulation of osteoclast migration and bone resorption by C–C chemokine ligands 19 and 21

Résumé

Osteoclasts are responsible for the bone erosion associated with rheumatoid arthritis (RA). The upregulation of the chemokines CCL19 and CCL21 and their receptor CCR7 has been linked to RA pathogenesis. The purpose of this study was to evaluate the effects of CCL19 and CCL21 on osteoclasts and to reveal their underlying mechanisms. The expression of CCL19, CCL21 and CCR7 was higher in RA patients than in osteoarthritis patients. In differentiating osteoclasts, tumor necrosis factor-α, interleukin-1β and lipopolysaccharide stimulated CCR7 expression. CCL19 and CCL21 promoted osteoclast migration and resorption activity. These effects were dependent on the presence of CCR7 and abolished by the inhibition of the Rho signaling pathway. CCL19 and CCL21 promoted bone resorption by osteoclasts in an in vivo mice calvarial model. These findings demonstrate for the first time that CCL19, CCL21 and CCR7 play important roles in bone destruction by increasing osteoclast migration and resorption activity. This study also suggests that the interaction of CCL19 and CCL21 with CCR7 is an effective strategic focus in developing therapeutics for alleviating inflammatory bone destruction. A signaling pathway responsible for inflammation-mediated bone degeneration may offer a good target for rheumatoid arthritis (RA) therapies. Bone is routinely ‘remodeled’ through degradation by cells known as osteoclasts, but this process spirals out of control in the joints of RA patients. Researchers led by Hong-Hee Kim at Korea's Seoul National University have found that RA-associated osteoclast activity is fueled by two signaling molecules, CCL19 and CCL21. They showed that these molecules and their receptor are produced in excess in the joints of RA patients. The researchers also demonstrated that signals generated via the receptor stimulate maturation and migration of osteoclasts, and drive aggressive bone erosion. Importantly, this process depends on the presence of inflammatory signals, a hallmark of RA. This may therefore represent a disease-specific mechanism that could be safely blocked with appropriate drugs.

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