Aging-induced decrease in progenitor B cells enhances the osteoclastogenesis of bone marrow macrophages via...

Area of Science:

• Immunology
• Bone Biology
• Gerontology

Background:

• Senile osteoporosis (SOP) poses a significant health challenge due to increased fracture risk in the elderly.
• The precise role of immune cell changes in SOP pathogenesis remains largely undefined.

Purpose of the Study:

• To elucidate the mechanistic link between immune cell alterations and senile osteoporosis.
• To investigate the impact of oxidative stress on immune cells within the bone marrow microenvironment in SOP.

Main Methods:

• Utilized senescence-accelerated mouse prone 6 (SAMP6) mice as an SOP model, compared to senescence-accelerated mouse resistant 1 (SAMR1) controls.
• Employed multi-omics (single-cell RNA sequencing, transcriptomics), flow cytometry, and histological analyses to study bone marrow immune cells.
• Investigated cell interactions and osteoclastogenesis in vitro, using a CCR1 antagonist (BX471) to block specific pathways.

Main Results:

• SAMP6 mice exhibited reduced bone mass and elevated reactive oxygen species (ROS).
• A significant depletion of B lymphocytes, particularly pro-B cells, was observed in SAMP6 mice.
• Oxidative stress induced the Fos/Ccl3 axis in pro-B cells, promoting osteoclastogenesis via the CCL3-CCR1 axis, an effect suppressed by BX471.

Conclusions:

• Elevated ROS accelerates B lymphocyte immune-senescence in SOP, reducing progenitor B cells.
• This process activates the Fos/Jun pathway, leading to CCL3 overexpression and enhanced macrophage osteoclastogenesis.
• Targeting the CCL3-CCR1 axis with antagonists offers a potential therapeutic strategy for senile osteoporosis.