Targeting Mitophagy as a Potential Therapeutic Approach for Age-Related Bone Diseases

Accumulating evidence has suggested a strong correlation between age-related bone diseases and abnormal metabolism of bone microenvironment-related cells, including mesenchymal stem cells (MSCs), osteoblasts, osteoclasts, osteocytes, and chondrocytes. Mitochondrial dysfunction significantly impacts cell metabolism and initiates the development and progress of numerous age-related bone diseases. Mitochondrial autophagy or mitophagy, a process that selectively removes damaged or dysfunctional mitochondria, is closely associated with maintaining mitochondrial quality control and homeostasis. Recent studies indicate a decisive regulatory role of mitophagy in age-related bone diseases, thereby pointing toward the potential for manipulating mitophagy levels as a new treatment paradigm. Based on the importance and novelty of mitophagy, the present review offers an overview of the pathways involved in mitophagy and meticulously examines its function in age-related bone diseases. Various treatment methods targeting mitophagy are also discussed, mainly including biomaterials with mitophagy-modulatory capabilities, "old drugs in a new bottle" (e.g., Metformin, Rapamycin), natural compounds, endogenous factors, and stem cell-based therapies. In conclusion, these innovative approaches uncover mitophagy-related signals, pathways, and mechanisms, and may shed light on mitophagy-targeting treatments for age-related bone diseases in the future. Mitophagy deficiency is a key mechanism in aging and age-related bone diseases (such as osteoporosis, osteoarthritis, intervertebral disc degeneration, and periodontitis), which hinders the removal of dysfunctional mitochondria and hence aggravates ROS and inflammation. Therapeutic approaches targeting mitophagy have significant potential for restoring normal bone metabolism or enhancing endogenous bone regeneration. image