{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:08:59Z","timestamp":1779210539208,"version":"3.51.4"},"reference-count":45,"publisher":"American Society for Clinical Investigation","issue":"9","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":64,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010975","name":"Pediatric Orthopaedic Society of North America","doi-asserted-by":"crossref","award":["822001"],"award-info":[{"award-number":["822001"]}],"id":[{"id":"10.13039\/100010975","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"crossref","award":["W81XWH-22-1-0576"],"award-info":[{"award-number":["W81XWH-22-1-0576"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["ZIA HD009024"],"award-info":[{"award-number":["ZIA HD009024"]}]},{"DOI":"10.13039\/100031886","name":"Scottish Rite for Children","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100031886","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:p>\n                    Osteofibrous dysplasia (OFD) is a skeletal RASopathy presenting with periosteal bone lesions that may progress to fracture and delayed healing (pseudarthrosis).\n                    <jats:italic>MET<\/jats:italic>\n                    gene mutations reducing ubiquitin-mediated protein degradation via loss of the juxtamembrane domain (MET\n                    <jats:sup>\u0394JMD<\/jats:sup>\n                    ) were previously identified in patients with OFD, resulting in ligand-dependent gain of function. The effect of\n                    <jats:italic>MET<\/jats:italic>\n                    <jats:sup>\u0394JMD<\/jats:sup>\n                    expression on skeletal progenitor cell differentiation and the potential efficacy of targeted therapies remain unclear. We engineered\n                    <jats:italic>Met<\/jats:italic>\n                    <jats:sup>\u0394JMD<\/jats:sup>\n                    mice and showed that\n                    <jats:italic>Met<\/jats:italic>\n                    <jats:sup>\u0394JMD<\/jats:sup>\n                    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\n                    <jats:italic>Met<\/jats:italic>\n                    enhanced osteogenic differentiation of periosteal progenitor cells. Inhibition of MAPK signaling with MEK inhibitors restored osteogenic differentiation of mouse\n                    <jats:italic>Met<\/jats:italic>\n                    <jats:sup>\u0394JMD<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci199048","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T17:00:15Z","timestamp":1772125215000},"source":"Crossref","is-referenced-by-count":0,"title":["MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy"],"prefix":"10.1172","volume":"136","author":[{"given":"Aysha B.","family":"Khalid","sequence":"first","affiliation":[{"name":"Center for Translational Research, Scottish Rite for Children, Dallas, Texas, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin","family":"Denton","sequence":"additional","affiliation":[{"name":"Center for Translational Research, Scottish Rite for Children, Dallas, Texas, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nandina","family":"Paria","sequence":"additional","affiliation":[{"name":"Center for Translational Research, Scottish Rite for Children, Dallas, Texas, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ila","family":"Oxendine","sequence":"additional","affiliation":[{"name":"Center for Translational Research, Scottish Rite for Children, Dallas, Texas, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meghan","family":"Wassell","sequence":"additional","affiliation":[{"name":"Center for Translational Research, Scottish Rite for Children, Dallas, Texas, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reuel","family":"Cornelia","sequence":"additional","affiliation":[{"name":"Center for Translational Research, Scottish Rite for Children, Dallas, Texas, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sasidhar","family":"Uppuganti","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffry S.","family":"Nyman","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA."},{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA."},{"name":"United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. Jayashree","family":"Jagadeesh","sequence":"additional","affiliation":[{"name":"Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos R.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-9259","authenticated-orcid":true,"given":"Simon J.","family":"Conway","sequence":"additional","affiliation":[{"name":"Herman B. 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