Rheumatoid arthritis (RA) is characterized by progressive joint destruction that is mediated by excessive bone erosion relative to new bone formation. This defect in bone turnover has mostly been attributed to osteoclast dysfunction, although some studies also indicate a defect in osteoblast function. A new study implicates subchondral bone marrow (SBM) B cells in controlling osteoblast dysfunction in RA.

“In prior work, we demonstrated that B cells from patients with RA are abnormal as they produce the cytokine RANKL in excess and promote osteoclast activation and bone erosion,” says corresponding author Jennifer Anolik.

Credit: Springer Nature Limited

In the new study, the researchers detected clusters of SBM B cells in close proximity to osteoblasts and areas of bone loss in TNF-transgenic mice and collagen-induced arthritis (CIA) models of RA. These B cells were phenotypically distinct from other bone marrow B cells, being mostly mature IgD+IgM+ cells expressing high levels of the osteoblast inhibitor TNF, the transcription factor DKK-3 and the chemokine CCL3.

The researchers also performed ectopic bone formation experiments by mixing mesenchymal progenitor cells (which can differentiate into osteoblasts) and SBM B cells and embedding them into Gelfoam (Pfizer), which was then implanted subcutaneously into SCID mice to assess bone formation in vivo. Compared with B cells from wild-type mice, B cells from TNF-transgenic mice mediated a decrease in bone volume in these assays. Importantly, this bone-loss phenotype was reversed when using SBM B cells from TNF-transgenic CCL3-knockout mice or from TNF-transgenic TNF-knockout mice, further supporting a critical function of TNF and CCL3 in SBM B cell inhibition of osteoblast function.

a critical function of TNF and CCL3

Providing evidence that these results are of human relevance, the researchers also detected synovial aggregates of B cells with high expression of CCL3 and TNF in patients with RA, and that these cells can inhibit osteoblast differentiation in culture.

Anolik and colleagues are now looking to extend this research to understand why these SBM B cells are pathogenic in RA. “Our next questions include how the joint microenvironment affects local B cell activation and dysfunction,” she concludes.