{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T14:21:05Z","timestamp":1787754065017,"version":"build-2784847793"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,5,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Delayed bone healing is common in orthopaedic clinical care. Agents that alter cell function to enhance healing would change treatment paradigms. 4-aminopyridine (4-AP) is a U.S. Food and Drug Administration (FDA)-approved drug shown to improve walking in patients with chronic neurological disorders. We recently showed 4-AP\u2019s positive effects in the setting of nerve, wound, and even combined multi-tissue limb injury. Here, we directly investigated the effects of 4-AP on bone fracture healing, where differentiation of mesenchymal stem cells into osteoblasts is crucial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>All animal experiments conformed to the protocols approved by the Institutional Animal Care and Use Committee at the University of Arizona and Pennsylvania State University. Ten-week-old C57BL\/6J male mice (22 to 28 g), following midshaft tibial fracture, were assigned to 4-AP (1.6 mg\/kg\/day, intraperitoneal [IP]) and saline solution (0.1 mL\/mouse\/day, IP) treatment groups. Tibiae were harvested on day 21 for micro-computed tomography (CT), 3-point bending tests, and histomorphological analyses. 4-AP\u2019s effect on human bone marrow mesenchymal stem cell (hBMSC) and human osteoblast (hOB) cell viability, migration, and proliferation; collagen deposition; matrix mineralization; and bone-forming gene\/protein expression analyses was assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      4-AP significantly upregulated BMP2 gene and protein expression and gene expression of RUNX2, OSX, BSP, OCN, and OPN in hBMSCs and hOBs. 4-AP significantly enhanced osteoblast migration and proliferation, collagen deposition, and matrix mineralization. Radiographic and micro-CT imaging confirmed 4-AP\u2019s benefit versus saline solution treatment in mouse tibial fracture healing (bone mineral density, 687.12 versus 488.29 mg hydroxyapatite\/cm\n                      <jats:sup>3<\/jats:sup>\n                      [p \u2264 0.0021]; bone volume\/tissue volume, 0.87 versus 0.72 [p \u2264 0.05]; trabecular number, 7.50 versus 5.78\/mm [p \u2264 0.05]; and trabecular thickness, 0.08 versus 0.06 mm [p \u2264 0.05]). Three-point bending tests demonstrated 4-AP\u2019s improvement of tibial fracture biomechanical properties versus saline solution (stiffness, 27.93 versus 14.30 N\/mm; p \u2264 0.05). 4-AP also increased endogenous BMP2 expression and matrix components in healing callus.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>4-AP increased the healing rate, biomechanical properties, and endogenous BMP2 expression of tibiae following fracture.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Level of Evidence:<\/jats:title>\n                    <jats:p>\n                      Prognostic\n                      <jats:underline>Level III<\/jats:underline>\n                      . See Instructions for Authors for a complete description of levels of evidence.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.2106\/jbjs.24.00311","type":"journal-article","created":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T20:36:29Z","timestamp":1742675789000},"page":"936-947","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":1,"title":["4-Aminopyridine Promotes BMP2 Expression and Accelerates Tibial Fracture Healing in Mice"],"prefix":"10.2106","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9551-4554","authenticated-orcid":false,"given":"Govindaraj","family":"Ellur","sequence":"first","affiliation":[{"name":"Department of Orthopaedics and Sports Medicine, University of Arizona College of Medicine, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8069-234X","authenticated-orcid":false,"given":"Prem Kumar","family":"Govindappa","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Sports Medicine, University of Arizona College of Medicine, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6462-8428","authenticated-orcid":false,"given":"Sandeep","family":"Subrahmanian","sequence":"additional","affiliation":[{"name":"Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2513-5046","authenticated-orcid":false,"given":"Gerardo Figueroa","family":"Romero","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Biomedical Engineering, University of Arizona College of Medicine, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0120-5761","authenticated-orcid":false,"given":"David A.","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Biomedical Engineering, University of Arizona College of Medicine, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2936-7506","authenticated-orcid":false,"given":"David S.","family":"Margolis","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Sports Medicine, University of Arizona College of Medicine, Tucson, Arizona"},{"name":"Department of Orthopaedic Surgery and Biomedical Engineering, University of Arizona College of Medicine, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4438-7118","authenticated-orcid":false,"given":"John C.","family":"Elfar","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Sports Medicine, University of Arizona College of Medicine, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"issue":"16","key":"bib2-20250509","doi-asserted-by":"crossref","first-page":"3554","DOI":"10.3390\/jcm10163554","article-title":"Insights into the Cellular and Molecular Mechanisms That Govern the Fracture-Healing Process: A Narrative Review","volume":"10","author":"Papachristou","year":"2021","journal-title":"J Clin 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