MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy
Aysha Khalid1, Kristin Denton1, Nandina Paria1
1Center for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
Abstract:
Osteofibrous dysplasia (OFD) is a skeletal RASopathy presenting with periosteal bone lesions that may progress to fracture and delayed healing (pseudarthrosis). MET gene mutations reducing ubiquitin-mediated protein degradation via loss of the juxtamembrane domain (METΔJMD) were previously identified in patients with OFD, resulting in ligand-dependent gain of function. The effect of METΔJMD expression on skeletal progenitor cell differentiation and the potential efficacy of targeted therapies remain unclear. We engineered MetΔJMD mice and showed that MetΔJMD expression inhibited osteogenic differentiation of skeletal progenitor cells in vitro and impaired cortical bone development and reduced bone stiffness in vivo. In contrast, conditional deletion of Met enhanced osteogenic differentiation of periosteal progenitor cells. Inhibition of MAPK signaling with MEK inhibitors restored osteogenic differentiation of mouse MetΔJMD skeletal progenitor cells and promoted the activation of transcriptional signatures associated with skeletal development and osteoblast differentiation in pseudarthrosis-derived primary cells from patients with OFD. With this preclinical support, we treated with the MEK inhibitor mirdametinib a pediatric patient with OFD who had a 3-year history of persistent pseudarthrosis, resulting in fracture union. Our findings demonstrate a bidirectional role for MET in regulating osteogenic differentiation of skeletal progenitor cells and a therapeutic avenue to improve clinical outcomes for this and potentially other skeletal RASopathies.
Insights
Osteofibrous dysplasia (OFD) is a skeletal RASopathy. MET gene mutations impair bone healing, but MEK inhibitors restored osteogenic differentiation and healed a patient's fracture.
Area of Science:
- Skeletal biology
- Genetics
- Molecular medicine
Background:
- Osteofibrous dysplasia (OFD) is a skeletal RASopathy characterized by periosteal lesions and impaired bone healing.
- MET gene mutations (METΔJMD) cause ligand-dependent gain-of-function, impacting skeletal progenitor cells, but their precise role and therapeutic targets are unknown.
Purpose of the Study:
- To investigate the impact of METΔJMD on skeletal progenitor cell differentiation.
- To evaluate the efficacy of MEK inhibitors as a targeted therapy for OFD.
Main Methods:
- Engineered MetΔJMD mice to study in vitro and in vivo effects on bone.
- Utilized MEK inhibitors to assess rescue of osteogenic differentiation in mouse and patient-derived cells.
- Administered mirdametinib to a pediatric OFD patient with persistent pseudarthrosis.
Main Results:
- MetΔJMD expression inhibited osteogenic differentiation and impaired bone development in mice.
- Conditional deletion of Met enhanced osteogenic differentiation.
- MEK inhibition restored osteogenic differentiation in MetΔJMD cells and patient cells, leading to fracture union in a treated patient.
Conclusions:
- MET plays a dual role in regulating osteogenic differentiation of skeletal progenitor cells.
- MEK inhibition represents a promising therapeutic strategy for Osteofibrous dysplasia and potentially other skeletal RASopathies.
