A RANKL+/CXCR4+ B cell population accumulates in bone marrow and causes age-related osteoporosis in mice

RANKL induces bone loss in part by promoting degradation of TRAF3, levels of which decrease in murine and human bone during aging, but the major cellular sources of RANKL in bone marrow (BM) during aging are unknown. Here, we identify RANKL⁺CXCR4⁺ B cells (RCBs) as a novel major source of RANKL in murine bone. Their numbers are increased in BM of aged WT male mice and adult mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs), associated with increased expression in BM of the chemokine, CXCL12, indicating that TRAF3 in MPCs limits RCB numbers in BM of young mice. During aging, TGFβ1-induced TRAF3 degradation in MPCs promotes NF-κB-mediated expression of CXCL12, associated with higher numbers of RCBs in BM where they induce bone resorption. In addition, RCBs from aged mice caused bone loss in young NSG mice and, in an ovariectomized mouse model, accelerated osteoclastic bone resorption coupled with TRAF3 reduction and RCB accumulation in BM. Consistent with these findings, administration of the FDA-approved CXCR4 Antagonist, plerixafor, reduced RCB numbers in BM and increased bone mass in naturally aged and ovariectomized mice. Reduction of RCB numbers in BM could treat/prevent osteoporosis.