NDR1 promotes osteoblast differentiation via PI3K-AKT signaling and Beclin-1‑associated autophagy

Nuclear Dbf2-related kinase 1 (NDR1), a Hippo-pathway protein kinase, regulates proliferation, apoptosis, and differentiation, but its role in bone homeostasis remains unclear. Here, we identified a novel role for NDR1 in maintaining physiological bone homeostasis by regulating osteoblast differentiation, but not osteoclastogenesis. Using NDR1 global knockout mice, primary osteoblast cultures, transcriptomics, and biochemical profiling, we demonstrated that deletion of NDR1 leads to decreased bone mass and impaired osteogenic differentiation capacity. Transcriptomic profiling revealed a significant enrichment of the PI3K–AKT signaling pathway in NDR1–deficient osteoblasts, indicating a potential mechanistic link. Moreover, we found that NDR1 physically interacts with Beclin-1 in osteoblasts, and NDR1 deletion was accompanied by downregulated Beclin-1 expression and reduced autophagic activity during osteoblast differentiation. Notably, pharmacological activation of PI3K–AKT with SC79 or enhancement of autophagy with rapamycin each partially rescued the osteogenic defects and bone loss in NDR1-KO mice. Together, our findings establish NDR1 as a novel regulator of bone formation and suggest its therapeutic potential for treating bone-related disorders such as osteoporosis.