{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:15:33Z","timestamp":1791832533242,"version":"4.3.4"},"reference-count":31,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,6]],"date-time":"2024-01-06T00:00:00Z","timestamp":1704499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fracture healing in the aged is associated with a reduced healing capacity, which often results in delayed healing or non-union formation. Many factors may contribute to this deterioration of bone regeneration, including a reduced \u2018angiogenic trauma response\u2019. The phosphodiesterase-3 (PDE-3) inhibitor cilostazol has been shown to exert pro-angiogenic and pro-osteogenic effects in preclinical studies. Therefore, we herein analyzed in a stable closed femoral fracture model whether this compound also promotes fracture healing in aged mice. Forty-two aged CD-1 mice (age: 16\u201318 months) were daily treated with 30 mg\/kg body weight cilostazol (n = 21) or vehicle (control, n = 21) by oral gavage. At 2 and 5 weeks after fracture, the femora were analyzed by X-ray, biomechanics, micro-computed tomography (\u00b5CT), histology, immunohistochemistry, and Western blotting. These analyses revealed a significantly increased bending stiffness at 2 weeks (2.2 \u00b1 0.4 vs. 4.3 \u00b1 0.7 N\/mm) and an enhanced bone formation at 5 weeks (4.4 \u00b1 0.7 vs. 9.1 \u00b1 0.7 mm3) in cilostazol-treated mice when compared to controls. This was associated with a higher number of newly formed CD31-positive microvessels (3.3 \u00b1 0.9 vs. 5.5 \u00b1 0.7 microvessels\/HPF) as well as an elevated expression of phosphoinositide-3-kinase (PI3K) (3.6 \u00b1 0.8 vs. 17.4 \u00b1 5.5-pixel intensity \u00d7 104) and runt-related transcription factor (RUNX)2 (6.4 \u00b1 1.2 vs. 18.2 \u00b1 2.7-pixel intensity \u00d7 104) within the callus tissue. These findings indicate that cilostazol accelerates fracture healing in aged mice by stimulating angiogenesis and the expression of PI3K and RUNX2. Hence, cilostazol may represent a promising compound to promote bone regeneration in geriatric patients.<\/jats:p>","DOI":"10.3390\/ijms25020755","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T07:59:20Z","timestamp":1704700760000},"page":"755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cilostazol Stimulates Angiogenesis and Accelerates Fracture Healing in Aged Male and Female Mice by Increasing the Expression of PI3K and RUNX2"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1261-9877","authenticated-orcid":false,"given":"Maximilian M.","family":"Menger","sequence":"first","affiliation":[{"name":"Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany"},{"name":"Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Emmerich","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Scheuer","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Hans","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4347-1702","authenticated-orcid":false,"given":"Sabrina","family":"Ehnert","sequence":"additional","affiliation":[{"name":"Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6666-6791","authenticated-orcid":false,"given":"Andreas K.","family":"N\u00fcssler","sequence":"additional","affiliation":[{"name":"Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Herath","sequence":"additional","affiliation":[{"name":"Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6549-9848","authenticated-orcid":false,"given":"Konrad","family":"Steinestel","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Menger","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Histing","sequence":"additional","affiliation":[{"name":"Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7847-8456","authenticated-orcid":false,"given":"Matthias W.","family":"Laschke","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13287-016-0300-9","article-title":"Aging, inflammation, stem cells, and bone healing","volume":"7","author":"Gibon","year":"2016","journal-title":"Stem Cell Res. 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