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Published on: March 15, 2018
A RANKL+/CXCR4+ B cell population accumulates in bone marrow and causes age-related osteoporosis in mice
Jinbo Li1,2,3, Jinxiao Fan4, Zhenqiang Yao5,6
1Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA. Jinbo_Li@hebmu.edu.cn.
Insights
Novel RANKL+CXCR4+ B cells (RCBs) drive bone loss in aging by increasing RANKL. Targeting these cells with CXCR4 antagonists may prevent or treat osteoporosis.
Area of Science:
- Bone Biology
- Immunology
- Aging Research
Background:
- Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL) drives bone loss, partly via Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3) degradation.
- TRAF3 levels decline in aging bone, but the cellular sources of RANKL in bone marrow during aging remain unidentified.
Purpose of the Study:
- To identify the major cellular sources of RANKL in the bone marrow during aging.
- To investigate the role of TRAF3 in mesenchymal progenitor cells (MPCs) in regulating RANKL-expressing B cells.
- To explore therapeutic strategies targeting these cells for osteoporosis treatment.
Main Methods:
- Identification of RANKL+CXCR4+ B cells (RCBs) as a novel source of RANKL in murine bone marrow.
- Analysis of RCB numbers in aged mice and mice with TRAF3-deficient MPCs.
- Assessment of the effects of RCBs from aged mice on bone loss in young recipient mice and an ovariectomized model.
- Evaluation of the efficacy of the CXCR4 antagonist plerixafor in aged and ovariectomized mice.
Main Results:
- RCBs were identified as a major source of RANKL in murine bone marrow, increasing with age.
- TRAF3 deficiency in MPCs led to increased CXCL12 and RCB accumulation in bone marrow.
- Aging-induced TRAF3 degradation in MPCs promoted CXCL12 expression, correlating with higher RCB numbers and bone resorption.
- Plerixafor treatment reduced RCBs and increased bone mass in aged and ovariectomized mice.
Conclusions:
- RANKL+CXCR4+ B cells (RCBs) are a significant source of RANKL in aging bone marrow.
- TRAF3 in mesenchymal progenitor cells plays a crucial role in limiting RCBs in young mice.
- Targeting CXCR4 with antagonists like plerixafor shows therapeutic potential for age-related bone loss and osteoporosis.
Abstract:
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.
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