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Atrophic nonunions are a subtype that are particularly difficult to treat. Animal models of atrophic nonunion are available; however, these require surgical or radiation-induced trauma to disrupt periosteal healing. These methods are invasive and not representative of many clinical nonunions where osseous regeneration has been arrested by a \u201cfailure of biology\u201d. We hypothesized that arresting osteoblast cell proliferation after fracture would lead to atrophic nonunion in mice. Using mice that express a thymidine kinase (tk) \u201csuicide gene\u201d driven by the 3.6Col1a1 promoter (Col1-tk), proliferating osteoblast lineage cells can be ablated upon exposure to the nucleoside analog ganciclovir (GCV). Wild-type (WT; control) and Col1-tk littermates were subjected to a full femur fracture and intramedullary fixation at 12\u2009weeks age. We confirmed abundant tk+ cells in fracture callus of Col-tk mice dosed with water or GCV, specifically many osteoblasts, osteocytes, and chondrocytes at the cartilage-bone interface. Histologically, we observed altered callus composition in Col1-tk mice at 2 and 3\u2009weeks postfracture, with significantly less bone and more fibrous tissue. Col1-tk mice, monitored for 12\u2009weeks with in vivo radiographs and micro\u2013computed tomography (\u03bcCT) scans, had delayed bone bridging and reduced callus size. After euthanasia, ex vivo \u03bcCT and histology showed failed union with residual bone fragments and fibrous tissue in Col1-tk mice. Biomechanical testing showed a failure to recover torsional strength in Col1-tk mice, in contrast to WT. Our data indicates that suppression of proliferating osteoblast-lineage cells for at least 2\u2009weeks after fracture blunts the formation and remodeling of a mineralized callus leading to a functional nonunion. We propose this as a new murine model of atrophic nonunion. \u00a9 2021 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4424","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T04:35:58Z","timestamp":1629261358000},"page":"2243-2257","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Ablation of Proliferating Osteoblast Lineage Cells After Fracture Leads to Atrophic Nonunion in a Mouse Model"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3094-5537","authenticated-orcid":false,"given":"Katherine R.","family":"Hixon","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Washington University in St. Louis St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"McKenzie","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Washington University in St. Louis St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8154-9921","authenticated-orcid":false,"given":"David A.W.","family":"Sykes","sequence":"additional","affiliation":[{"name":"Department of Biology Washington University in St. Louis St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Yoneda","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Washington University in St. Louis St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Hensley","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Washington University in St. Louis St. Louis MO USA"},{"name":"Department of Orthopaedic Surgery Washington University in St. Louis St. Louis MO 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8433-4224","authenticated-orcid":false,"given":"Audrey","family":"McAlinden","sequence":"additional","affiliation":[{"name":"St. Louis Shriners Hospital Research Center Shriners Hospital for Children St. Louis MO USA"},{"name":"Department of Cell Biology & Physiology Washington University in St. Louis St. Louis MO USA"},{"name":"Department of Orthopaedic Surgery Washington University in St. Louis St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7056-8502","authenticated-orcid":false,"given":"Anna N.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Washington University in St. Louis St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7375-4522","authenticated-orcid":false,"given":"Matthew 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