Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function
Julia F. Charles, … , Antonios O. Aliprantis, Mary C. Nakamura
Julia F. Charles, … , Antonios O. Aliprantis, Mary C. Nakamura
Published November 1, 2012
Citation Information: J Clin Invest. 2012;122(12):4592-4605. https://doi.org/10.1172/JCI60920.
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Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function

Abstract

Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b–/loLy6Chi BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4+ T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4+ and CD8+ T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell–suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint.

Authors

Julia F. Charles, Lih-Yun Hsu, Erene C. Niemi, Arthur Weiss, Antonios O. Aliprantis, Mary C. Nakamura

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Figure 3

CD11b–/loLy6ChiCX3CR1+ OCPs are distinct from other myeloid precursors.

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CD11b–/loLy6ChiCX3CR1+ OCPs are distinct from other myeloid precursors. ...
(A–C) FACS analysis of cell-surface markers on CD3–B220–Ter119– gated BM from CX3CR1-GFPhet distinguishes OCP from other myeloid populations. Staining of CD11bloLy6Chi CX3CR1 OCP population with the indicated antibody (lines) compared with isotype control (gray area) is shown. (A) OCPs are predominantly CD115+. (B) OCPs are CD135loCD117+/–, further distinguishing them from CD11b–Ly6C–MDPs (CD135+CD117+, dashed line) and CD11b+Ly6Chi M1 monocytes (CD135–CD117–, dark gray line). (C) Both CD117+ and CD117– subsets are capable of differentiating into osteoclasts in vitro, although those in the CD117+ subset are more efficient. TRAP+ multinuclear osteoclast formed per 1 × 103 cells cultured in triplicate in M-CSF/RANKL, *P = 0.03. (D) OCPs are CD11c–, in contrast with pre-DCs (CD11b+CX3CR1+CD11c+, dotted line). (E) GST-RANKL-biotin (black line) or GST-biotin control (gray area) demonstrate RANK expression on the surface of BM-derived day 2 osteoclasts (right panel) but not OCPs (left panel). Loss of osteoclast-binding RANKL-GST-bio binding in the presence of excess unlabeled RANKL (dashed line) demonstrates specificity. (F) Model of myeloid differentiation with the CD11b–/loLy6ChiCX3CR1+CD115+ OCP as distinct myeloid precursors derived from MDPs; Mo, monocyte; QOP, lineage committed QOP.