Doxorubicin Induces Bone Loss by Increasing Autophagy through a Mitochondrial ROS/TRPML1/TFEB Axis in Osteoclasts

Area of Science:

• Oncology
• Cell Biology
• Bone Biology

Background:

• Doxorubicin (DOX), a chemotherapy drug, is associated with bone damage in patients and bone loss in mice.
• Autophagy, a cellular process, plays a role in bone homeostasis, but excessive autophagy in osteoclasts (OCs) contributes to bone loss.

Purpose of the Study:

• To investigate the hypothesis that Doxorubicin-induced bone loss is caused by the induction of autophagy in osteoclasts.
• To elucidate the molecular mechanisms underlying DOX-induced autophagy and bone loss.

Main Methods:

• In vitro studies using osteoclasts to assess DOX effects on cell area, bone resorption, apoptosis, and autophagy markers (LC3II, acidic vesicular organelles).
• In vivo studies using micro-computerized tomography and tartrate-resistant acid phosphatase staining in mice treated with DOX and/or 3-methyladenine (3-MA).
• Investigated the role of mitochondrial reactive oxygen species (mROS), TRPML1, and TFEB in the DOX-induced autophagy pathway.

Main Results:

• In vitro, DOX increased OC area and bone resorption but decreased OC number via apoptosis. DOX enhanced autophagy markers, which were reversed by the autophagy inhibitor 3-MA.
• DOX increased mROS, leading to TRPML1 oxidation and nuclear translocation of TFEB, an autophagy-inducing transcription factor.
• In vivo, 3-MA treatment reversed DOX-induced bone loss and reduced OC area on the bone surface.

Conclusions:

• Doxorubicin-induced bone loss is partly mediated by autophagy upregulation in osteoclasts.
• The mROS/TRPML1/TFEB signaling pathway is crucial for DOX-induced autophagy and subsequent bone loss.
• Inhibiting autophagy with 3-MA may be a potential strategy to mitigate Doxorubicin-induced bone damage.