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

  • Authors:
    • Shuhong Zhang
    • Ge Yang
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    Affiliations: Department of Orthopedics, Key Laboratory of Pediatric Orthopedics of Hunan Province, Hunan Children's Hospital, Affiliated Children's Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410007, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
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    Published online on: July 14, 2026
       https://doi.org/10.3892/ijmm.2026.5929
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Abstract

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.
View Figures

Figure 1

Schematic representation of the human
NF1 gene and domains within the neurofibromin protein. The upper
image shows the structure of the human NF1 gene, which is located
at chromosome 17q11.2 and spans ~350 kb. The locus comprises an
upstream promoter/regulatory region, followed by the 5' UTR and a
complex gene body containing 60 exons separated by introns (not
shown). Several alternatively spliced exons, including exon 9a
(light purple), exon 10a-2 (orange), exon 23a (green) and exon 48a
(blue), contribute to NF1 transcript diversity. Neurofibromin
contains multiple functional regions, including a CSRD, a GRD, a
Sec, a PH and a CTD. The GRD functions as a GTPase-activating
domain that accelerates conversion of active RAS-GTP to inactive
RAS-GDP, thereby negatively regulating RAS signaling and
suppressing cell growth. NF1, neurofibromatosis type 1; UTR,
untranslated region; CSRD, cysteine/serine-rich domain; GRD,
GAP-related domain; Sec, Sec14 domain; PH, pleckstrin homologous
domain; CTD, C-terminal domain; GTP, guanosine triphosphate; GDP,
guanosine diphosphate; TBD, tubulin-binding domain.

Figure 2

Cellular impacts of neurofibromin
deficiency on bone homeostasis. Neurofibromin deficiency disrupts
bone homeostasis through cell-type-specific effects on osteoblasts,
osteoclasts, osteocytes and chondrocytes. Research using
fracture-derived stromal cells from patients with NF1 and with
somatic NF1 loss show that a complete loss of NF1 allows early
osteogenic specification, but impairs later functional maturation,
indicating a block in the transition from lineage commitment to
mature bone-forming activity. NF1-haploinsufficient mesenchymal
stromal cells derived from human-induced pluripotent stem cells
display impaired osteoblast differentiation and reduced matrix
mineralization, demonstrating that partial NF1 loss is sufficient
to compromise osteogenic capacity. In mouse models with
osteoblast-specific Nf1 ablation, neurofibromin deficiency causes
pyrophosphate accumulation, which inhibits hydroxyapatite crystal
formation and contributes to reduced bone mineral density. NF1 loss
also affects bone-resorbing and matrix-embedded skeletal cells. In
murine NF1-haploinsufficient osteoclasts, hyperactivation of
RAS/PI3K signaling increases responsiveness to M-CSF and RANKL,
resulting in enhanced osteoclast differentiation and accelerated
osteolytic activity. Osteocytes with a complete loss of Nf1 in mice
exhibit cytoplasmic vacuolization and disorganization of the
perilacunar matrix, suggesting impaired osteoid mineralization. In
cartilage, unrestrained RAS-ERK1/2 signaling inhibits chondrocyte
maturation and endochondral ossification, thereby interfering with
normal skeletal growth and repair. Together, these findings from
patient-derived cells and genetically engineered mouse models
indicate that neurofibromin deficiency impairs both bone formation
and bone resorption control, providing a cellular basis for the
diverse skeletal abnormalities observed in NF1. NF1,
neurofibromatosis type 1; M-CSF, macrophage colony-stimulating
factor; RANKL, receptor activator of NF-κB ligand; MSCs,
mesenchymal stem cells.

Figure 3

Pathogenesis of osteopenia and
osteoporosis in patients with NF1. Individuals with NF1 frequently
exhibit reduced BMD, particularly in the lumbar spine and femur,
which contributes to increased fracture susceptibility and often
co-occurs with vitamin D deficiency. Histological and microarchi-
tectural analyses of NF1-associated osteopenia and osteoporosis
have demonstrated impaired bone structure, including reduced
trabecular bone. Mechanistic research using NF1-related mouse and
cellular models has further indicated that bone loss is associated
with increased bone turnover and enhanced osteoclast activity. In
Nf1flox/-; Col2.3Cre mice, hyperactivation of TGF-β1
signaling promotes osteoclast activation and pathological bone
resorption. Nf1+/- osteoblasts secrete elevated levels
of osteopontin, which further stimulates osteoclasts and
contributes to excessive bone degradation. Additional evidence from
adult osteoprogenitor-specific MAPK pathway models, including
Mek1Osx-ERTMek2-/- mice, has shown that
disruption of downstream ERK signaling within the RAS/MAPK cascade
markedly reduces BMD, highlighting the importance of NF1-regulated
signaling in maintaining skeletal homeostasis. Together, these
findings support a pathogenic model in which NF1-associated
dysregulation of osteoblast-osteoclast coupling drives
high-turnover bone loss, reduced BMD and increased fracture risk.
NF1, neurofibromatosis type 1; BMD, bone mineral density.

Figure 4

Pathology and molecular mechanisms
driving NF1-associated CPT. CPT is characterized by anterolateral
bowing deformity, pseudarthrosis and thickened periosteum, which
gives rise to fibrous hamartoma tissue that mechanically and
biologically interferes with fracture repair. Cellular and
molecular research have indicated that this lesion originates from
aberrant NF1-haploinsufficient periosteal cells, which exhibit
impaired terminal osteoblastic differen- tiation, and a phenotypic
shift toward myofibroblastic and chondrogenic lineages. These
defects reduce the osteogenic capacity of the periosteum and
promote fibrotic tissue accumulation at the nonunion site. Genetic
and histological analyses have further suggested that somatic NF1
inactivation is enriched in the soft tissue component of CPT
lesions. In addition to impaired bone formation, enhanced
osteoclastogenesis and increased bone resorption contribute to
cortical erosion and create a biological barrier to union.
Proteomic and molecular profiling studies have identified
dysregulated signaling pathways and tissue abnor- malities,
including aberrant PI3K/AKT signaling, vascular narrowing and
disorganized extracellular matrix architecture. Together, these
findings indicate that NF1-associated CPT results from the
convergence of defective periosteal osteogenesis, fibrotic
hamartoma invasion, excessive osteoclast-mediated bone resorption,
abnormal vascular supply and disrupted matrix organization. NF1,
neurofibromatosis type 1; CPT, congenital pseudarthrosis of the
tibia.

Figure 5

Clinical classification and cellular
pathogenesis of NF1-associated scoliosis. NF1-associated scoliosis
is generally classified into dystrophic and non-dystrophic forms,
which differ in radiographic features, progression pattern and
clinical risk. Dystrophic scoliosis represents the characteristic
spinal deformity in NF1, and is typically marked by early onset,
rapid progression and frequent involvement of the upper thoracic
spine. By contrast, non-dystrophic scoliosis may initially resemble
adolescent idiopathic scoliosis but can progress. Non-dystrophic
scoliosis is associated with an increased risk of complications,
including pseudarthrosis after spinal fusion. In addition to focal
spinal deformity, patients with NF1 often exhibit systemic reduced
BMD, with the lumbar spine disproportionately affected, suggesting
that spinal instability occurs in the context of generalized
skeletal fragility. At the cellular and molecular levels,
neurofibromin deficiency disrupts key signaling pathways that
regulate vertebral bone remodeling, including RAS/MAPK and TGF-β1
signaling cascades. These changes promote abnormal osteoclast
proliferation, impair osteoblast differentiation and alter collagen
biosynthesis. Together, these abnormalities disturb vertebral bone
homeostasis, and provide a mechanistic basis for reduced BMD,
progressive spinal deformity, impaired fusion biology and the
clinical severity of NF1-associated scoliosis. NF1,
neurofibromatosis type 1; BMD, bone mineral density.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang S and Yang G: Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review). Int J Mol Med 58: 258, 2026.
APA
Zhang, S., & Yang, G. (2026). Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review). International Journal of Molecular Medicine, 58, 258. https://doi.org/10.3892/ijmm.2026.5929
MLA
Zhang, S., Yang, G."Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review)". International Journal of Molecular Medicine 58.3 (2026): 258.
Chicago
Zhang, S., Yang, G."Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review)". International Journal of Molecular Medicine 58, no. 3 (2026): 258. https://doi.org/10.3892/ijmm.2026.5929
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang S and Yang G: Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review). Int J Mol Med 58: 258, 2026.
APA
Zhang, S., & Yang, G. (2026). Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review). International Journal of Molecular Medicine, 58, 258. https://doi.org/10.3892/ijmm.2026.5929
MLA
Zhang, S., Yang, G."Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review)". International Journal of Molecular Medicine 58.3 (2026): 258.
Chicago
Zhang, S., Yang, G."Neurofibromin in bone disease: Mechanisms and therapeutic implications (Review)". International Journal of Molecular Medicine 58, no. 3 (2026): 258. https://doi.org/10.3892/ijmm.2026.5929
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