Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function
Julia F. Charles, Lih-Yun Hsu, Erene C. Niemi, Arthur Weiss, Antonios O. Aliprantis, Mary C. Nakamura
Julia F. Charles, Lih-Yun Hsu, Erene C. Niemi, Arthur Weiss, Antonios O. Aliprantis, Mary C. Nakamura
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Research Article Autoimmunity

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 7

CD11bloLy6Chi OCPs have cell-surface markers of MDSCs and suppress in vitro T cell proliferation.

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CD11bloLy6Chi OCPs have cell-surface markers of MDSCs and suppress in vi...
(A) Wright-Giemsa stain of sorted OCPs cultured for 48 hours in M-CSF demonstrates monocytic nuclear morphology and characteristic gray blue cytoplasm. Original magnification, ×20. (B) Similar to MDSCs, BM CD11bloLy6Chi OCPs are CD49d and CD124 positive. Antibody-specific staining of cells gated on CD3–B220–Ter119–CD11b–/loLy6Chi is shown in black line, isotype staining in gray area. (C) CD11b–/loLy6Chi OCPs purified from SKG BM suppress CD4+ T cell proliferation (light gray bars) in contrast with CD11b+Ly6C+ (white bar) or QN (dark gray bar) populations from the same BM. Data are representative of 3 independent experiments. (D) CD11bloLy6Chi OCPs sorted from C57BL/6 CX3CR1:GFPhet BM based on CX3CR1 expression demonstrate that, similar to osteoclast precursor potential, suppressor activity is seen in the CX3CR1+ (light gray bars) but not CX3CR1– (dark gray bar) population. (E) Inhibition of T cell proliferation by freshly isolated OCPs is maintained after differentiation of sorted OCPs in the presence of M-CSF and 100 ng/ml RANKL for 4 days. Addition of RANKL to proliferation medium does not significantly inhibit proliferation (white bar), whereas cultured OCPs retain suppressive activity (gray bars). (F) There is no significant difference in suppressor activity between OCPs derived from BALB/c mice (dark gray bars) and those from arthritic SKG mice (light gray bars).