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 8

Suppression of CD4+ T cell proliferation by CD11bloLy6Chi OCPs requires NOS2, caspase activity, and IFN-γ.

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Suppression of CD4+ T cell proliferation by CD11bloLy6Chi OCPs requires ...
(A) Full suppression of T cell proliferation requires cell-cell contact. Maximal CD4+ T cell proliferation (black bars) is inhibited by CD11b–/loLy6Chi OCPs in the lower chamber (gray bars) more efficiently than OCPs in upper chamber (striped) in Transwell assays.**P = 0.02; *P = 0.035. (B) Suppression of T cell proliferation by OCP is not relieved by OPG. A ratio of 1:4 OCP/T cell inhibits proliferation (gray bars) compared with T cells alone (black bars). OPG at concentrations from 25–200 ng/ml had no effect. (C) CD4+ T cell proliferation (black bars) is suppressed by OCPs at a ratio of 1:4 (gray bars). The addition of the NOS2 inhibitor L-NIL or blocking antibody to IFN-γ relieves suppression compared with isotype/DMSO control. Inhibition of IL-10, arginase, and IDO have no effect. (D) OCPs from Nos2–/– mice (light gray bars) have decreased T cell–suppressive activity compared with C57BL/6 OCPs (dark gray bars). (E) OCPs express the IFN-γ receptor α-chain (black line) compared with isotype control (gray area). (F–H) T cell–derived IFN-γ and intact IFN-γ signaling in OCPs is required for suppression. (F) Proliferation of wild-type CD4+ T cells (black bar) is suppressed by OCP derived from C57BL/6 (light gray bars) or Ifng–/– mice (striped bars) over a range of ratios from 1:2 to 1:8. In contrast, OCPs derived from Ifngr–/– mice (dark gray bars) do not suppress. (G) Proliferation of Ifngr–/– CD4+ T cells (black bar) is similarly inhibited by wild-type and Ifng–/– OCPs, but not Ifngr–/– OCP Ifng–/–. (H) Proliferation of Ifng–/– T cells (black bar) is not inhibited by OCPs of any genotype.