MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy
Aysha B. Khalid, Kristin Denton, Nandina Paria, Ila Oxendine, Meghan Wassell, Reuel Cornelia, Sasidhar Uppuganti, Jeffry S. Nyman, G. Jayashree Jagadeesh, Carlos R. Ferreira, Simon J. Conway, Robert E. Hammer, John Ritter, Mylinh Nguyen, David A. Podeszwa, Laura J. Klesse, Carol A. Wise, Jonathan J. Rios
Aysha B. Khalid, Kristin Denton, Nandina Paria, Ila Oxendine, Meghan Wassell, Reuel Cornelia, Sasidhar Uppuganti, Jeffry S. Nyman, G. Jayashree Jagadeesh, Carlos R. Ferreira, Simon J. Conway, Robert E. Hammer, John Ritter, Mylinh Nguyen, David A. Podeszwa, Laura J. Klesse, Carol A. Wise, Jonathan J. Rios
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Research Article Bone biology Clinical Research Genetics

MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy

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.

Authors

Aysha B. Khalid, Kristin Denton, Nandina Paria, Ila Oxendine, Meghan Wassell, Reuel Cornelia, Sasidhar Uppuganti, Jeffry S. Nyman, G. Jayashree Jagadeesh, Carlos R. Ferreira, Simon J. Conway, Robert E. Hammer, John Ritter, Mylinh Nguyen, David A. Podeszwa, Laura J. Klesse, Carol A. Wise, Jonathan J. Rios

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Figure 5

Mirdametinib improves pseudarthrosis healing in a patient with OFD.

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Mirdametinib improves pseudarthrosis healing in a patient with OFD. (A a...
(A and B) Representative Western blot (A) and quantification (B) demonstrating a dose-dependent reduction in ERK pathway activation in OFD patient pseudarthrosis–derived primary cells (n = 5) treated with mirdametinib. Triangles indicate samples with somatic MET mutations; circles indicate samples without detectable MET mutations. Quantification data are presented as the mean ± SEM, with statistically significant differences determined by 1-way ANOVA with Dunnett’s multiple-test correction. (C) Principal component (PC) analysis of OFD patient pseudarthrosis–derived primary cells treated with vehicle or mirdametinib (n = 5). (D and E) Volcano plot (D) and heatmap (E) of genes differentially expressed between mirdametinib- and vehicle-treated OFD patient pseudarthrosis–derived primary cells. Exp., expression. (F and G) GO analysis of differentially expressed genes with increased (F) and decreased (G) expression following mirdametinib treatment. activ., activity; coll., collagen; diff., differentiation; phosph., phosphotase; reg., regulation; struct., structure; sys. develop., system development. (H and I) Longitudinal postoperative radiographs of an OFD patient’s pseudarthrosis treated without mirdametinib (H) and with mirdametinib (I). **P < 0.01, ***P < 0.001, and ****P < 0.0001.