RAS-MAPK inhibition halts spinal deformity in neurofibromatosis type 1 mouse model

Spinal deformities such as scoliosis and kyphosis are among the most serious complications of neurofibromatosis type 1 (NF1), a genetic disorder that affects about one in 3,000 people. These deformities often begin in childhood, worsen rapidly, and can lead to chronic pain, reduced mobility, and may require major surgery. Despite their frequency and severity, there are currently no approved drug treatments to prevent NF1-related spinal deformity.

In a new study published in Volume 13, Issue 103 of the journal Bone Research on December 16, 2025, a research team lead by Dr. Céline Colnot from Univ Paris Est Creteil in France set out to identify the cellular origin and biological mechanism behind this condition. They used a genetically engineered mouse model, known as the Prss56-Nf1 knockout mouse, which reproduces multiple NF1 symptoms, including tumors, bone abnormalities, and spinal curvature.

Using high-resolution micro-CT imaging, the researchers showed that the mice developed progressive spinal deformities beginning in adulthood, with vertebral changes closely resembling those seen in patients with NF1. By genetically labeling affected cells, the team traced the abnormalities to an unexpected source: bone-forming osteoblasts carrying mutations in the NF1 gene.

"Our data show that NF1-deficient osteoblasts accumulate in the vertebrae and are directly linked to the severity of the spinal curvature," says Dr. Colnot. "The more mutant bone cells present, the more pronounced the deformity becomes."

Further analyses revealed that these osteoblasts remain locked in an abnormally active state due to persistent activation of the RAS-MAPK signaling pathway, which regulates cell growth and differentiation. As a result, bone formation and resorption become imbalanced, leading to excessive and disorganized bone buildup within the spine.

"These cells continue to proliferate and fail to mature properly," says Dr. Colnot. "Over the time, this disrupts the normal architecture of the vertebrae and contributes to spinal curvature."

Because the RAS–MAPK pathway is already targeted by drugs used to treat certain NF1-related tumors, the researchers tested whether blocking this signal could prevent spinal deformity. When adult mutant mice were treated with a combination of selumetinib and RMC-4550, MEK/SHP2 inhibitors, the progression of spinal deformities was halted.

"Pharmacological inhibition of this pathway prevented spine deformity in our model," the authors note, highlighting the potential of repurposing existing drugs for NF1-related skeletal disease.

The researchers caution that their findings are limited to mice and further studies are needed to determine whether similar mechanisms drive spinal deformity in people with NF1. Nonetheless, their work offers hope for understanding, and eventually treating, a condition that currently leaves patients with few options beyond monitoring and surgery.