# Chemotherapy-induced adipo-lineage cell senescence drives bone loss

## TL;DR

Chemotherapy causes bone loss by making bone marrow fat cells age, but targeting these aged cells can prevent the damage.

## Contribution

The study identifies adipo-lineage cell senescence as a novel mechanism of chemotherapy-induced bone loss and proposes a therapeutic strategy.

## Key findings

- Chemotherapy causes senescence in bone marrow adipo-lineage cells, leading to bone loss.
- Inhibiting the p38MAPK-MK2 pathway reduces bone loss by suppressing the SASP and RANKL production.
- Senolytic treatment with D + Q eliminates senescent cells and prevents chemotherapy-induced bone loss.

## Abstract

Chemotherapy-induced bone loss is a debilitating and common side effect of cancer treatment, though its underlying mechanisms remain poorly understood. Here, we show that, despite the systemic administration of chemotherapy, cellular senescence is restricted to bone marrow adipo-lineage cells specifically Cxcl12-abundant reticular (CAR) cells and bone marrow adipocytes (BMAds). Induction of senescence within these populations promotes RANK ligand (RANKL)-mediated osteoclastogenesis, leading to significant bone loss. Notably, we find that inhibition of the p38MAPK-MK2 pathway suppresses the senescence-associated secretory phenotype (SASP), including RANKL production abrogating bone loss. Furthermore, treatment with the senolytic combination dasatinib and quercetin (D + Q) selectively eliminates senescent CAR cells and BMAds, effectively preventing chemotherapy-induced bone loss. Given that nearly all chemotherapy treated patients experience bone loss and associated fracture risk, our findings offer a promising therapeutic avenue to preserve bone integrity and improve quality of life for cancer patients.

Chemotherapy induces bone loss that compromises skeletal health in cancer patients. Here, the authors show that chemotherapy-induced senescence in bone marrow adipo-lineage cells leads to bone loss and demonstrate that senolytic targeting of senescent cells preserves skeletal health during chemotherapy, providing a potential strategy to protect the skeleton in cancer therapy.