{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T09:54:40Z","timestamp":1792403680531,"version":"4.4.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2007,3,1]],"date-time":"2007-03-01T00:00:00Z","timestamp":1172707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>HIF-1\u03b1 activates genes under hypoxia and was hypothesized to regulate bone regeneration. Surprisingly, HIF-1\u03b1+\/\u2212 fracture calluses are larger, stronger, and stiffer than HIF-1\u03b1+\/+ calluses because of decreased apoptosis. These data identify apoptosis inhibition as a means to enhance bone regeneration.<\/jats:p>\n               <jats:p>Introduction: Bone regeneration subsequent to fracture involves the synergistic activation of multiple signaling pathways. Localized hypoxia after fracture activates hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1), leading to increased expression of HIF-1 target genes. We therefore hypothesized that HIF-1\u03b1 is a key regulator of bone regeneration.<\/jats:p>\n               <jats:p>Materials and Methods: Fixed femoral fractures were generated in mice with partial HIF-1\u03b1 deficiency (HIF-1\u03b1+\/\u2212) and wildtype littermates (HIF-1\u03b1+\/+). Fracture calluses and intact contralateral femurs from postfracture days (PFDs) 21 and 28 (N = 5\u201310) were subjected to \u03bcCT evaluation and four-point bending to assess morphometric and mechanical properties. Molecular analyses were carried out on PFD 7, 10, and 14 samples (N = 3) to determine differential gene expression at both mRNA and protein levels. Finally, TUNEL staining was performed on PFD 14 samples (N = 2) to elucidate differential apoptosis.<\/jats:p>\n               <jats:p>Results: Surprisingly, fracture calluses from HIF-1\u03b1+\/\u2212 mice exhibited greater mineralization and were larger, stronger, and stiffer. Microarray analyses focused on hypoxia-induced genes revealed differential expression (between genotypes) of several genes associated with the apoptotic pathway. Real-time PCR confirmed these results, showing higher expression of proapoptotic protein phosphatase 2a (PP2A) and lower expression of anti-apoptotic B-cell leukemia\/lymphoma 2 (BCL2) in HIF-1\u03b1+\/+ calluses. Subsequent TUNEL staining showed that HIF-1\u03b1+\/+ calluses contained larger numbers of TUNEL+ chondrocytes and osteoblasts than HIF-1\u03b1+\/\u2212 calluses.<\/jats:p>\n               <jats:p>Conclusions: We conclude that partial HIF-1\u03b1 deficiency results in decreased chondrocytic and osteoblastic apoptosis, thereby allowing the development of larger, stiffer calluses and enhancing bone regeneration. Furthermore, apoptosis inhibition may be a promising target for developing new treatments to accelerate bone regeneration.<\/jats:p>","DOI":"10.1359\/jbmr.061207","type":"journal-article","created":{"date-parts":[[2006,12,20]],"date-time":"2006-12-20T14:52:37Z","timestamp":1166626357000},"page":"366-374","source":"Crossref","is-referenced-by-count":60,"title":["Enhanced Bone Regeneration Associated With Decreased Apoptosis in Mice With Partial HIF-1\u03b1 Deficiency"],"prefix":"10.1093","volume":"22","author":[{"given":"David E","family":"Komatsu","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Bosch-Marce","sequence":"additional","affiliation":[{"name":"Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 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