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.
View: Text | PDF
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

×

Figure 2

The CD11b–/loLy6ChiCX3CR1+ population contains the majority of osteoclast precursor activity.

Options: View larger image (or click on image) Download as PowerPoint
The CD11b–/loLy6ChiCX3CR1+ population contains the majority of osteoclas...
(A–C) Individual BM populations from SKG mice, sorted by CD11b and Ly6C staining as illustrated in A, were plated in triplicate at 2.5 × 103/well in M-CSF and RANKL. (B) Multinucleated TRAP+ cells were counted after 3 days, and (C) resorption pits on osteologic slides were quantitated after 14 days culture. The purity of each sorted population is stated in parenthesis in the x axis label. Results are representative of 4 independent experiments. (D) TRAP staining of CD11b–/loLy6Chi OCPs cocultured with BM stromal cell–derived osteoblasts demonstrates osteoclast formation that is absent in parallel osteoblast-only culture. (E) Original magnification, ×10. (F) CX3CR1 expression is variable in the CD11b–/loLy6Chi population. CX3CR1 expression by CD11b–/loLy6ChiCD3–B220–Ter119– gated BM from CX3CR1-GFPhet mice (black line) compared with C57BL/6 (gray area). (G) Triplicate cultures of 1 × 103 cells/well in M-CSF and RANKL demonstrates that only the CX3CR1+CD11b–/loLy6Chi population efficiently differentiates into multinucleated TRAP+ osteoclasts and (H) forms resorption pits on osteologic slides. Original magnification, ×4. Results are representative of 3 replicates. (I) CD11b–/loLy6ChiCX3CR1+ cells retain the ability to form osteoclast after long-term culture. The total number of colonies obtained from single cells sorted from the indicated populations after 60 days in culture is indicated by column height, with the number retaining osteoclast differentiation capacity denoted in gray.