{"doi":"10.3390/ijms25020755","title":"Cilostazol Stimulates Angiogenesis and Accelerates Fracture Healing in Aged Male and Female Mice by Increasing the Expression of PI3K and RUNX2","abstract":"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 ‘angiogenic trauma response’. 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: 16–18 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 (µCT), histology, immunohistochemistry, and Western blotting. These analyses revealed a significantly increased bending stiffness at 2 weeks (2.2 ± 0.4 vs. 4.3 ± 0.7 N/mm) and an enhanced bone formation at 5 weeks (4.4 ± 0.7 vs. 9.1 ± 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 ± 0.9 vs. 5.5 ± 0.7 microvessels/HPF) as well as an elevated expression of phosphoinositide-3-kinase (PI3K) (3.6 ± 0.8 vs. 17.4 ± 5.5-pixel intensity × 104) and runt-related transcription factor (RUNX)2 (6.4 ± 1.2 vs. 18.2 ± 2.7-pixel intensity × 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.","journal":"International Journal of Molecular Sciences","year":2024,"id":453935,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9412,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1277178,"name":"Maximilian Emmerich","orcid":null,"position":2,"is_corresponding":false},{"id":1277179,"name":"Cláudia Scheuer","orcid":null,"position":3,"is_corresponding":false},{"id":1277180,"name":"Sandra Hans","orcid":null,"position":4,"is_corresponding":false},{"id":1276779,"name":"Sabrina Ehnert","orcid":"0000-0003-4347-1702","position":5,"is_corresponding":false},{"id":1276780,"name":"Andreas K. Nüssler","orcid":"0000-0002-6666-6791","position":6,"is_corresponding":false},{"id":1276781,"name":"Steven C. Herath","orcid":"0000-0003-4213-8676","position":7,"is_corresponding":false},{"id":1276782,"name":"Konrad Steinestel","orcid":"0000-0002-6549-9848","position":8,"is_corresponding":false},{"id":1276783,"name":"Michael D. Menger","orcid":"0000-0002-9670-7961","position":9,"is_corresponding":false},{"id":1276784,"name":"Tina Histing","orcid":"0000-0002-6955-2001","position":11,"is_corresponding":false},{"id":940888,"name":"Matthias W. Laschke","orcid":"0000-0002-7847-8456","position":12,"is_corresponding":false},{"id":1276778,"name":"Maximilian M. Menger","orcid":"0000-0002-1261-9877","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T02:03:03.428151Z","pmid":"38255829","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}