Abstract
Detailed characterization of medullary and extramedullary reservoirs of osteoclast progenitors (OCPs) is required to understand the pathophysiology of increased periarticular and systemic bone resorption in arthritis. In this study, we focused on identifying the OCP population specifically induced by arthritis and the role of circulatory OCPs in inflammatory bone loss. In addition, we determined the relevant chemokine axis responsible for their migration, and targeted the attraction signal to reduce bone resorption in murine collagen-induced arthritis (CIA). OCPs were expanded in periarticular as well as circulatory compartment of arthritic mice, particularly the CCR2hi subset. This subset demonstrated enhanced osteoclastogenic activity in arthritis, whereas its migratory potential was susceptible to CCR2 blockade in vitro. Intravascular compartment of the periarticular area contained increased frequency of OCPs with the ability to home to the arthritic bone, as demonstrated in vivo by intravascular staining and adoptive transfer of splenic LysMcre/Ai9 tdTomato-expressing cells. Simultaneously, CCL2 levels were increased locally and systemically in arthritic mice. Mouse cohorts were treated with the small-molecule inhibitor (SMI) of CCR2 alone or in combination with methotrexate (MTX). Preventive CCR2/CCL2 axis blockade in vivo reduced bone resorption and OCP frequency, whereas combining with MTX treatment also decreased disease clinical score, number of active osteoclasts, and OCP differentiation potential. In conclusion, our study characterized the functional properties of two distinct OCP subsets in CIA, based on their CCR2 expression levels, implying that the CCR2hi circulatory-like subset is specifically induced by arthritis. Signaling through the CCL2/CCR2 axis contributes to OCP homing in the inflamed joints and to their increased osteoclastogenic potential. Therefore, addition of CCL2/CCR2 blockade early in the course of arthritis is a promising approach to reduce bone pathology.
Highlights
Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune inflammatory disease affecting 1% of the population worldwide [1]
The frequency of osteoclast progenitor (OCP), identified as CD3-B220-NK1.1-CD11b-/loCD115+ cells in periarticular tissues and CD3-B220-NK1.1-CD11b+CD115+ cells in peripheral tissues (SPL and peripheral blood (PBL)) (Figure 1B), was increased among hematopoietic CD45+ cells in arthritis (Figure 1C)
Since we previously showed that a substantial proportion of human peripheral blood OCPs express chemokine receptors, CCR2 and CXCR3 [13], we applied a similar experimental design to verify the role of corresponding ligands CCL2 and CXCL10, respectively, in human OCP migration
Summary
Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune inflammatory disease affecting 1% of the population worldwide [1]. During inflammation-induced bone resorption, there is an established osteoclast activity in places far from the hematopoietically active bone marrow. It is, clear that OCPs must migrate to bone surfaces either within a bone or via bloodstream, to engage in bone resorption [10, 11]. Clear that OCPs must migrate to bone surfaces either within a bone or via bloodstream, to engage in bone resorption [10, 11] It remains unclear whether osteoclasts derive predominantly from circulating monocytes or bone marrowresident progenitors [12]. A recent review by Yahara et al suggests that additional studies are needed to reveal the mechanisms that orchestrate the mobilization of circulating OCPs from the extramedullary organs to bone in pathologic or homeostatic conditions [9]
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