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ResearchIn-Press PreviewBone biologyClinical ResearchGenetics Open Access | 10.1172/JCI199048

MEK inhibitor Mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy

Aysha Khalid,1 Kristin Denton,1 Nandina Paria,1 Ila Oxendine,1 Meghan Wassell,1 Reuel Cornelia,1 Sasidhar Uppuganti,2 Jeffry S. Nyman,2 G. Jayashree Jagadeesh,3 Carlos R. Ferreira,3 Simon J. Conway,4 Robert E. Hammer,5 John O. Ritter,5 Mylinh Nguyen,5 David A. Podeszwa,6 Laura J. Klesse,7 Carol A. Wise,1 and Jonathan J. Rios1

1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Khalid, A. in: PubMed | Google Scholar

1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Nguyen, M. in: PubMed | Google Scholar

1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Podeszwa, D. in: PubMed | Google Scholar

1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

Find articles by Wise, C. in: PubMed | Google Scholar |

1Center for Translational Research, Scottish Rite for Children, Dallas, United States of America

2Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, United States of America

3Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States of America

4Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States of America

5Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States of America

6Department of Orthopaedics, Scottish Rite for Children, Dallas, United States of America

7Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

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Published February 26, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI199048.
Copyright © 2026, Khalid et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 26, 2026 - Version history
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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 OFD patients, resulting in ligand-dependent gain-of-function. The impact 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 activation of transcriptional signatures associated with skeletal development and osteoblast differentiation in OFD patient pseudarthrosis-derived primary cells. With this preclinical support, we treated with the MEK inhibitor mirdametinib a pediatric OFD patient suffering from a 3-year history of persistent pseudarthrosis, resulting in fracture union. Our findings demonstrate a bi-directional role for MET in regulating osteogenic differentiation of skeletal progenitor cells and a therapeutic avenue to improve clinical outcomes for this, and potential other, skeletal RASopathies. 

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  • Version 1 (February 26, 2026): In-Press Preview
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