Updating the pathophysiology of arthritic bone destruction: identifying and visualizing pathological osteoclasts in pannus

Abstract

Osteoclasts have a unique capacity to destroy bone, playing key roles in physiological bone remodeling and arthritic bone erosion. It is not known whether the osteoclast populations in different tissue settings arise from similar monocytoid precursors. The rapid progress in the next-generation sequencing technologies has provided many valuable insights into the field of osteoimmunology, and single-cell RNA sequencing (scRNA-Seq) can elucidate cellular heterogeneity within the synovial microenvironment. The application of scRNA-Seq to the defined osteoclast precursor (OP)-containing population enabled the identification of individual cells differentiating into mature osteoclasts in the inflamed synovium, which were distinct from conventional OPs in the bone marrow. In addition, an intravital imaging system using multi-photon microscopy has been applied to the synovial tissues of arthritic mice to observe the real-time dynamics of osteoclasts and immune cells in the pannus. These technologies have contributed to elucidate the transcriptomics and dynamics of specific cells involved in pathological osteoclastogenesis, improving our understand of the pathophysiology of inflammatory osteolytic diseases. Here, we review how novel technologies such as scRNA-Seq and intravital imaging help to better understand the pathogenesis of bone erosion and we introduce recent studies that have identified and directly visualized pathological OPs in inflamed synovium.

New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis

“…In the CIA murine model, 10% of AtoMs from the pannus (i.e., inflamed synovium) of mice differentiated into mature OCs. 148 Intravital imaging analysis of the pannus–bone interface confirmed that some AtoMs were OCPs transitioning into mature OCs. These OCs actively resorbed the bone matrix without migrating to the bone surface, 148 unlike physiological BM OCs, which are in close contact with osteoblasts and migrate slowly to the bone surface.…”

“… 148 Intravital imaging analysis of the pannus–bone interface confirmed that some AtoMs were OCPs transitioning into mature OCs. These OCs actively resorbed the bone matrix without migrating to the bone surface, 148 unlike physiological BM OCs, which are in close contact with osteoblasts and migrate slowly to the bone surface. 149 In addition, therapy targeting AtoMs (thiostrepton, an inhibitor of FOXM1 activity) resulted in a decrease in bone erosion in CIA mice without affecting homeostatic bone remodeling in healthy mice, both in vitro and in vivo.…”