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Patients with NF1 present with pleiotropic somatic secondary manifestations, including development of bone pseudarthrosis after fracture. Somatic NF1 gene mutations were reproducibly identified in patient-derived pseudarthrosis specimens, suggesting a local mosaic cell population including somatic pathologic cells. The somatic cellular pathogenesis of NF1 pseudarthroses remains unclear, though defects in osteogenesis have been posited. Here, we applied time-series single-cell RNA-sequencing (scRNA-seq) to patient-matched control and pseudarthrosis-derived primary bone stromal cells (BSCs). We show that osteogenic specification to an osteoblast progenitor cell population was evident for control bone-derived cells and haploinsufficient pseudarthrosis-derived cells. Similar results were observed for somatic patient fracture-derived NF1\u2212\/\u2212 cells; however, expression of genetic pathways associated with skeletal mineralization were significantly reduced in NF1\u2212\/\u2212 cells compared with fracture-derived NF1+\/\u2212 cells. In mice, we show that Nf1 expressed in bone marrow osteoprogenitors is required for the maintenance of the adult skeleton. Results from our study implicate impaired Clec11a-Itga11-Wnt signaling in the pathogenesis of NF1-associated skeletal disease. \u00a9 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4755","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T10:09:25Z","timestamp":1669975765000},"page":"288-299","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Molecular Dissection of Somatic Skeletal Disease in Neurofibromatosis Type 1"],"prefix":"10.1093","volume":"38","author":[{"given":"Nandina","family":"Paria","sequence":"first","affiliation":[{"name":"Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysha","family":"Khalid","sequence":"additional","affiliation":[{"name":"Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children Dallas TX 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