Background Bone resorption is a severe problem associated with inflammatory disease like periodontitis and rheumatoid arthritis. Osteoclasts, cells responsible for bone resorption, have been shown to be affected by some cytokines and chemokines. However, whether CCL19 and CCL21 chemokines have any role in the regulation of osteoclast differentiation or activation has not yet been investigated.
Objectives The purpose of this study was to examine the potential role of CCL19 and CCL21 chemokines and their recepor CCR7 in the differentiation and/or activation of osteoclasts.
Methods To evaluate the mRNA expression levels of CCL19 and CCL21 and their receptor CCR7 in rheumatoid arthritis and osteoarthritis patients, the microarray results deposited to gene expression omnibus were retrieved and analyzed. The expression levels of these molecules and differentiation markers in osteoclasts were measured by real time polymerase chain reaction, western blotting or flow cytometry. Cell migration was quantified by a transwell assay. Resorption activity was performed on the calcium phosphate-coated dish or dentin slice and analyzed by von Kossa staining or confocal microscopy. Collagen transplantation model was used to examine the in vivo effects of these cytokines.
Results The expression levels of CCL19, CCL21 and CCR7 were higher in rheumatoid arthritis than in osteoarthritis patients. Bone marrow macrophages and osteoclasts expressed more CCR7 in response to inflammatory stimuli TNFalpha, IL-1beta and LPS. CCL19 and CCL21 promoted the migration of both bone marrow macrophages and osteoclasts and resorption activity of osteoclasts. CCL19 and CCL21 activated Rho and its downstream ROCK via CCR7. CCR7 siRNA and ROCK inhibition negated the effects of CCL19 and CCL21. Administration of CCL19 and CCL21 onto calvarial bones of mice in the collagen transplantation model showed that these cytokines can promote the bone resorption in vivo.
Conclusions This study demonstrates that CCL19 and CCL21 chemokines increase osteoclast migration and resorption activity via CCR7 and intracellular Rho-ROCK signaling. As these chemokines present at a high level in rheumatoid arthritis patients, CCL19 and CCL21 may play important roles in bone destruction associated with rheumatoid arthritis.
Disclosure of Interest None declared