Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review)

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by pathogenic mutations in the NF1 gene, which encodes neurofibromin, a critical tumor suppressor and regulator of intracellular signaling. NF1 is a multisystem disease characterized by café‑au‑lait macules, neurofibromas, learning disabilities and prominent skeletal abnormalities. Accumulating evidence has demonstrated that neurofibromin is essential for maintaining skeletal homeostasis and a loss of neurofibromin results in dysregulated signaling pathways, particularly RAS/MAPK and PI3K/AKT. This dysregulation leads to NF1‑associated skeletal diseases, such as low bone mineral density, osteoporosis, congenital pseudarthrosis of the tibia and scoliosis through disordered bone remodeling. Despite substantial progress being made in elucidating the molecular and cellular mechanisms underlying NF1‑associated skeletal diseases, clinical management remains challenging. Skeletal abnormalities often present early in childhood and may progress despite intervention, highlighting the need for timely and effective assessment strategies. Current treatments for NF1 rely largely on complex surgical reconstruction and supportive medical therapy, with variable long‑term outcomes. The present review summarizes the current understanding of the role of neurofibromin in bone homeostasis, discusses the cellular and molecular mechanisms driving NF1‑associated skeletal diseases, and examines emerging assessment tools and therapeutic strategies. Furthermore, future directions aimed at translating mechanistic insights into improved clinical outcomes for patients with NF1‑associated skeletal diseases are outlined.