Osteoclasts are important for both homeostatic bone remodelling in health and pathological bone erosion in rheumatoid arthritis (RA), but whether different types of osteoclasts mediate these two processes is unclear. New findings suggest that osteoclasts in these different tissue settings arise from different precursor cells and hence follow distinct developmental trajectories.
To identify osteoclast precursor cells in the synovium, researchers in a new study developed a protocol that enabled them to isolate synovium from ‘bare areas’ of the joint (areas where the synovium comes into contact with bone). They detected a subpopulation of macrophages (termed arthritis-associated osteoclastogenic macrophages (AtoMs)) in the inflamed synovium of mice with collagen-induced arthritis (CIA). This population contained osteoclast precursors that were phenotypically distinct from osteoclast precursors involved in homeostatic bone remodelling in the bone marrow.
Transcriptional profiling implicated the transcription factor FOXM1 as an important regulator of AtoMs. Indeed, treatment with thiostrepton (an inhibitor of FOXM1 activity) inhibited osteoclastogenesis of AtoMs in vitro. In mice with CIA, thiostrepton treatment reduced the arthritis scores of the mice and inhibited the expression of pro-inflammatory cytokines in the synovium. However, in healthy mice, thiostrepton had no effect on homeostatic bone remodelling.
In mice with collagen antibody-induced arthritis, tamoxifen-mediated deletion of Foxm1 alleviated bone erosion and partially reduced the arthritis scores of the mice. Adoptive transfer of Foxm1-expressing monocytes partially reversed these effects.
Notably, the researchers identified a population of macrophages in the synovium of patients with RA that corresponded to mouse AToMs. The cells expressed FOXM1 and had a high osteoclastogenic potential that was inhibited with thiostrepton in vitro.
the cells expressed FOXM1 and had a high osteoclastogenic potential
The researchers plan to develop a novel therapy that specifically targets these ‘bad’ osteoclast precursors. “Because current regimens for treating bone diseases block both ‘good’ and ‘bad’ osteoclasts, a new line of therapy targeting only ‘bad’ ones would be meritorious for future patient care,” explains corresponding author Masaru Ishii.
Hasegawa, T. et al. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nat. Immunol. 20, 1631–1643 (2019)
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McHugh, J. Precursors of ‘bad’ osteoclasts identified in arthritis. Nat Rev Rheumatol 16, 63 (2020). https://doi.org/10.1038/s41584-019-0362-z
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