FOXO1-mTOR pathway in vascular pericyte regulates the formation of type H vessels to control bone metabolism.

Background: As the population aging progresses, age-related osteoporosis has become one of the most common and severe chronic degenerative diseases. Due to insufficient understanding of its complex pathomechanisms, current clinical treatments often suffer from many negative effects. Type H vessels play critical role in bone remodeling owing to their specialized function in coupling angiogenesis and osteogenesis. Increasing evidences have shown a close association between the age-related decline of type H vessels and bone loss. However, the underlying mechanisms whereby the regression of type H vessels with aging remain largely unknown. Methods: Results: This study identified FOXO1 in pericytes as key components for the formation of type H vessels. We found that FOXO1 expression in pericytes decreases with aging, and pharmacological blocking with AS1842856 promoted type H vessels degeneration and increased bone loss in adult and middle-aged mice, while rapamycin prevented the above pathology in middle-aged mice. We further showed that the loss of FOXO1 in Conclusion: Our findings uncover a hitherto unknown role of FOXO1 in maintaining the phenotype and function of pericytes, thereby promoting formation of type H vessels. This suggests that targeting the FOXO1-mTOR pathway in pericytes could be a potential therapeutic approach to overcome the regression of type H vessels and bone degeneration with aging. The translational potential of this article: Our research uncovers a previously unidentified role of FOXO1 in preserving pericyte characteristics and promoting the development of type H vessels. Future translational research targeting the FOXO1-mTOR pathway in pericytes may provide new strategies for the prevention and treatment of age-related osteoporosis in the clinic.