Abstract
Abstract Osteoclasts, specialized bone resorbing cells of hematopoietic origin, become overactive in rheumatoid arthritis, leading to bone loss and joint destruction. Osteoclast progenitor cells (OCP) arise from myeloid precursors of monocyte/macrophage lineage and are found in the bone marrow and among circulatory monocytes. Under inflammatory conditions subpopulations of OCPs undergo through functional and phenotypic changes responsible for their increased migration to inflamed sites and osteoresorptive activity. In our study, we have been investigating frequencies of distinct OCP subsets and their expression of chemokine receptors in circulation and periarticular bone marrow (PBM) of C57BL/6 mice with collagen-induced arthritis (CIA). We found that both hematopoietic lymphoid-negative CD11b+CD115+ and CD11b−/loCD115+ subsets possess osteoclastogenic activity and are enlarged in blood and PBM of affected joints in CIA. OCP subsets substantially expressed CCR2 and CX3CR1, but had low expression of CCR5, CCR9 and CXCR4, with no difference between control and CIA group. Concurrently CCL2 serum levels were significantly increased in CIA, whereas CX3CL1 levels were comparable to control. In an in vitro migration assay, peripheral blood leukocytes from CIA mice after M-CSF and RANKL stimulation increasingly migrated toward CCL2 and CCL5 chemotactic gradients. Intravascular in vivo staining demonstrated increased recirculation of CD45+CD11b+ cells through areas of PBM affected by arthritis. These results suggest that highly induced OCP subpopulations in CIA migrate to inflamed joints due to chemotaxis and therefore blocking of chemokine signals may reduce osteoclast activity in arthritis.
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