ABSTRACT The increasing prevalence of age‐related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age‐related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1‐cKO) mice as a premature aging model and found that MACF1‐cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β‐catenin was enhanced, increasing the transcriptional activity of the FoxO1/β‐catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β‐catenin pathway competitively weakens the binding of β‐catenin to TCF7 and decreases the activity of the TCF7/β‐catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β‐catenin fate and regulate osteoblast differentiation during senile osteoporosis.
Su et al. (2025) studied this question.