Evidence map›Paper›PMID 41746735›Full record

ArticleThe Journal of clinical investigation2026

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 and 8 more

Abstract read
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In one paragraph

Article in The Journal of clinical investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Aysha B KhalidCenter for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
Kristin DentonCenter for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
Nandina PariaCenter for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
Ila OxendineCenter for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
Meghan WassellCenter for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
Reuel CorneliaCenter for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
Sasidhar UppugantiDepartment of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Jeffry S NymanDepartment of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
G Jayashree JagadeeshUnit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
Carlos R FerreiraUnit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
Simon J ConwayHerman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Robert E HammerDepartment of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
John RitterDepartment of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
Mylinh NguyenDepartment of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
David A PodeszwaDepartment of Orthopaedics, Scottish Rite for Children, Dallas, Texas, USA.
Laura J KlesseDepartment of Pediatrics, and.
Carol A WiseCenter for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
Jonathan J RiosCenter for Translational Research, Scottish Rite for Children, Dallas, Texas, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

AminopyridinesFracture HealingProtein Kinase InhibitorsPseudarthrosisAnimalsCell DifferentiationChildFemaleHumansMiceOsteogenesisAminopyridinesProtein Kinase InhibitorsBone biologyBone diseaseClinical ResearchDrug therapyGenetics

Identifiers

PMID41746735
PMCPMC13132394

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.