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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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 1

Erosive arthritis, generalized bone loss, and increased BM OCPs in SKG arthritis.

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Erosive arthritis, generalized bone loss, and increased BM OCPs in SKG a...
(A–C) μCT analysis of female SKG mice with chronic arthritis (SKG-A) compared with healthy littermate controls (SKG-c) shows erosions and generalized bone loss. (A) Representative 3D reconstructions of rear paw, showing erosions (asterisks) and (B) representative images and quantitation of BV/TV of proximal tibia metaphysis and (C) cortical thickness, n = 4 per group. *P ≤ 0.03, Mann-Whitney test. (D) BM from SKG mice after 8 weeks arthritis shows increased osteoclast differentiation. BM cells derived from arthritic or control SKG mice, n = 4 each group, were cultured in M-CSF and RANKL and number of TRAP-stained multinuclear (MN) osteoclasts were quantified from triplicate wells of 2.5 × 103 cells plated from each individual, P = 0.03 Mann-Whitney test. A representative image of TRAP-stained cultures is shown. Original magnification, ×10. Data are representative of 3 experiments. (E) Representative dot plot showing an increased BM B220–CD3–CD11b–/loLy6Chi population in arthritic mice. Surface phenotype of CD11b–/loLy6Chi cells is Ly6G– Gr1+. (F) CD11b–/loLy6Chi cells sorted from SKG BM are enriched for OCPs compared with the CD3–B220–Ter119– input; triplicate cultures of 12.5 × 103 cells were plated in M-CSF and RANKL for 3 days. Representative images are shown. Original magnification, ×10. (G) The CD11b–/loLy6Chi population increases in percentage (top) and total number (bottom) in SKG mice after 8 weeks arthritis compared with healthy littermate controls or age-matched BALB/c controls. P < 0.005, 1-way ANOVA. Representative data from 3 independent experiments are shown.