Spinal deformities, including scoliosis and kyphosis, are significant complications in people with neurofibromatosis type 1 (NF1), a genetic disorder affecting approximately one in 3,000 individuals. These spinal issues often begin during childhood and can progress rapidly, leading to chronic pain and reduced mobility. Currently, there are no approved drug therapies to prevent or treat these skeletal problems associated with NF1.
A study published on December 16, 2025, in Bone Research by Dr. Céline Colnot and her team at Univ Paris Est Creteil examined the origins and mechanisms behind NF1-related spinal deformities. The researchers used a genetically engineered mouse model called the Prss56-Nf1 knockout mouse that exhibits several symptoms of NF1, such as tumors, bone abnormalities, and spine curvature.
Through high-resolution micro-CT imaging, the team observed that these mice developed progressive spinal deformities starting in adulthood. The vertebral changes closely matched those seen in human patients with NF1. By labeling specific cells genetically, they traced the problem to osteoblasts—bone-forming cells—with 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."
Additional analysis revealed that these osteoblasts were stuck in an overactive state due to ongoing activation of the RAS-MAPK signaling pathway—a key regulator of cell growth and differentiation. This abnormal activity disrupted normal bone formation and resorption processes within the spine.
"These cells continue to proliferate and fail to mature properly," says Dr. Colnot. "Over time, this disrupts the normal architecture of the vertebrae and contributes to spinal curvature."
Since drugs targeting the RAS–MAPK pathway are already used for some NF1-related tumors, researchers tested whether blocking this pathway could stop spinal deformity progression. Treatment of adult mutant mice with MEK/SHP2 inhibitors selumetinib and RMC-4550 halted further development of spine problems.
"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 research team notes their findings are limited to animal models at this stage; more studies will be needed before applying similar treatments for people with NF1-related spinal deformities. However, these results may lead toward new treatment options beyond current monitoring or surgical interventions.
