Targeting angiogenin as a therapeutic strategy for age-related osteoporosis

With aging, the accumulation of cellular stress and cellular senescence drives the progression of osteoporosis. As a conserved cellular stress response, angiogenin (ANG) induces the cleavage of cytoplasmic transfer RNAs (tRNAs) to generate tRNA-derived stress-induced RNAs (tiRNAs) with diverse functional roles in various diseases. However, their biological functions in regulating osteoporosis remain poorly understood. In our study, we observed that angiogenin levels increase in senescent Bone Marrow Stromal Cells (BMSCs), and that angiogenin promotes age-dependent accumulation of 5'-tiRNA-Glu ^-CTC by cleaving tRNA-Glu under oxidative stress. The 5'-tiRNA-Glu ^-CTC disrupts the stability of anti-senescence and pro-osteogenic mRNAs, leading to bone-fat imbalance and thereby accelerating bone loss. Blocking 5'-tiRNA-Glu ^-CTC wiht antisense oligonucleotide (ASO) or inhibiting angiogenin with NCI-65828 alleviates BMSCs senescence and age-related bone loss. Clinical sample detection and analysis revealed that elevated serum levels of 5'-tiRNA-Glu ^-CTC in patients with osteoporosis exhibit a positive correlation with bone resorption markers and a negative correlation with bone formation markers. These findings suggest that 5'-tiRNA-Glu ^-CTC may serve as a potential biomarker for diagnosing age-related osteoporosis. Collectively, our study sheds new light on the role of ANG-induced 5'-tiRNAs in regulating BMSCs senescence and highlights angiogenin as a promising therapeutic target for age-related osteoporosis.