While nuclear factor I/A (NFIA) is well-established to function in brain development, its role in bone homeostasis remains unexplored. This study aims to explore its association with osteoporosis and its impact on bone mass. A down-regulation of Nfia expression was observed in the bone marrow stromal cells from senile osteoporotic women and aged mice, linking NFIA deficiency to age-related bone loss. Notably, conditional deletion of Nfia in osteoprogenitor cells (KO- Nfia Osx ) or in mesenchymal cells (KO- Nfia Prx1 ), but not in osteoblasts (KO- Nfia Col1 ), led to a decrease in bone mass accrual in adult mice, indicating that NFIA acts primarily in mesenchymal stem/progenitor cells rather than in relatively mature osteoblasts. In KO- Nfia Osx mice, numbers of osteoblasts and osteoclasts were increased while adipocyte numbers decreased, with enhanced bone resorption predominating over bone formation, leading to impaired bone mass accrual. Bone marrow stromal cells from KO- Nfia Osx mice showed enhanced osteogenic differentiation, reduced adipogenesis, and greater capacity to support osteoclast formation, confirming the dual but unbalanced effects. Mechanistically, NFIA suppresses osteoclast differentiation by transcriptionally down-regulating RANKL, while it inhibits osteoblast differentiation and promotes adipogenesis by transcriptionally up-regulating SFRP1, thereby inactivating Wnt/β-catenin signaling. This study provides the first evidence that NFIA is a crucial regulator of bone homeostasis: its expression in mesenchymal stem/progenitor cells inhibits both bone resorption and formation, with a more pronounced impact on resorption. Since its down-regulation disrupts bone balance and tends to reduce bone mass, maintaining an appropriate NFIA level is critical for bone health.
Dong et al. (Sun,) studied this question.