The Effects of Desferroxamine on Bone and Bone Graft Healing in Critical-Size Bone Defects

Guzey, Serbulent; Aykan, Andaç; Öztürk, Serdar; Avsever, Hakan; Karslioğlu, Yıldırım; Ertan, Atilla

doi:10.1097/sap.0000000000000679

Cited by 8 publications

(10 citation statements)

References 28 publications

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“…Previous studies have consistently shown the therapeutic effects of DFO on bone loss in a variety of conditions [21][22][23]. Accelerated bone regeneration was also observed in the bone defect model when treated with DFO locally or systemically [24,25]. In an ovariectomy (OVX)-induced osteoporotic mouse model, DFO administration prevented bone loss to a certain extent and maintained the microstructure of bone trabeculae [26].…”

Section: Discussionmentioning

confidence: 90%

Intraperitoneal injection of Desferal® alleviated the age-related bone loss and senescence of bone marrow stromal cells in rats

et al. 2021

Stem Cell Res Ther

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Background Age-related bone loss plays a vital role in the development of osteoporosis and osteoporotic fracture. Bone marrow stromal cell (BMSC) senescence is highly associated with osteoporosis and limits the application of BMSCs in regenerative medicine. Hypoxia is an essential component for maintaining the normal physiology of BMSCs. We have reported that activation of hypoxia-induced factor by deletion of von Hippel-Lindau gene in osteochondral progenitor cells protected mice from aging-induced bone loss. However, whether pharmacologically manipulation of hypoxic niche would attenuate age-related bone loss and dysfunction of BMSCs is not well understood. Methods Twelve-month-old Sprague-Dawley rats were used as an aged model and were intraperitoneally injected with Desferal® (20, 60 mg/kg weight or vehicle), three times a week for a continuous 8-week period. Two-month-old young rats were set as a reference. After 8 weeks, micro-CT and HE staining were performed to determine the effect of Desferal® on bone loss. In order to investigate the effects of Desferal® on BMSC senescence, 12-month-old rats were treated with high-dose Desferal® (60 mg/kg weight) daily for 10 days. BMSCs were isolated and evaluated using CCK-8 assay, colony-forming cell assay, cell differentiation assay, laser confocal for reactive oxygen species (ROS) level, senescence-associated β-galactosidase (SA-β-gal) staining, and molecular expression test for stemness/senescence-associated genes. Results Micro-CT and HE staining showed that high-dose Desferal® significantly prevented bone loss in aged rats. Compared with vehicle group, the ex vivo experiments showed that short-term Desferal® administration could promote the potential of BMSC growth (proliferation and colony formation ability) and improve the rebalance of osteogenic and adipogenic differentiation, as well as rejuvenate senescent BMSCs (ROS level and SA-β-gal staining) and revise the expression of stemness/senescence-associated genes. The potential of BMSCs from 12M-H-Desferal® group at least partly revised to the level close to 2-month-old group. Conclusions The current study suggested that Desferal®, an iron-chelating agent, could alleviate age-related bone loss in middle-aged rats. Meanwhile, we found that short-term intraperitoneal injection of Desferal® partly rejuvenate BMSCs from aged rats. Overall, we demonstrated a novel role of Desferal® in rejuvenating aged BMSCs and preventing age-related bone loss.

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Section: Discussionmentioning

confidence: 90%

Intraperitoneal injection of Desferal® alleviated the age-related bone loss and senescence of bone marrow stromal cells in rats

et al. 2021

Stem Cell Res Ther

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“…DFO showed encouraging results for bone repair in a variety of preclinical animal studies [19, 26, 56]. However, it is critical to understand the roles of DFO in BMP2- induced bone regeneration and thereby develop appropriate delivery strategies for further applications.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is critical to understand the roles of DFO in BMP2- induced bone regeneration and thereby develop appropriate delivery strategies for further applications. As a potent HIF-1α activator, DFO strongly promotes angiogenesis through producing angiogenic factors [18, 23], which is thought to be the main contribution of DFO to improved bone regeneration [26, 56, 57]. The common strategy for dual-delivery of BMPs and angiogenic factors is relatively short/fast/early release for angiogenic factors while sustained/slow/late release for BMPs because angiogenesis and vascularization are prerequisite s for bone healing process [58, 59].…”

Section: Discussionmentioning

confidence: 99%

“…Deferoxamine (DFO), a FDA-approved iron chelator for iron overload diseases, is a potent hypoxia-mimetic agent by inhibiting the activity of Prolyl Hydroxylase enzyme (PHD), which is the key enzyme responsible for the degradation of HIF-1α [24, 25]. DFO has shown promise in promoting bone repair by improving angiogenesis [19, 20, 26]. However, high cytotoxicity, off- target effects, and the short half- life of DFO have significantly limited its further applications [27, 28].…”

Section: Introductionmentioning

confidence: 99%

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Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering

Yao

Liu

Selvaratnam

et al. 2018

Journal of Controlled Release

111

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Controlled delivery systems play a critical role in the success of bone morphogenetic proteins (i.e., BMP2 and BMP7) for challenged bone repair. Instead of single-drug release that is currently and commonly prevalent, dual-drug delivery strategies are highly desired to achieve effective bone regeneration because natural bone repair process is driven by multiple factors. Particularly, angiogenesis is essential for osteogenesis and requires more than just one factor (e.g., Vascular Endothelial Growth Factor, VEGF). Therefore, we developed a novel mesoporous silicate nanoparticles (MSNs) incorporated-3D nanofibrous gelatin (GF) scaffold for dual-delivery of BMP2 and deferoxamine (DFO). DFO is a hypoxia-mimetic drug that can activate hypoxia-inducible factor-1 alpha (HIF-1α), and trigger subsequent angiogenesis. Sustained BMP2 release system was achieved through encapsulation into large-pored MSNs, while the relative short-term release of DFO was engineered through covalent conjugation with chitosan to reduce its cytotoxicity and elongate its half-life. Both MSNs and DFO were incorporated onto a porous 3D GF scaffold to serve as a biomimetic osteogenic microenvironment. Our data indicated that DFO and BMP2 were released from a scaffold at different release rates (10 vs 28 days) yet maintained their angiogenic and osteogenic ability, respectively. Importantly, our data indicated that the released DFO significantly improved BMP2-induced osteogenic differentiation where the dose/duration was important for its effects in both mouse and human stem cell models. Thus, we developed a novel and tunable MSNs/GF 3D scaffold-mediated dual-drug delivery system and studied the potential application of the both FDA-approved DFO and BMP2 for bone tissue engineering.

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“…134,144 Furthermore, proangiogenic growth factors and compounds, which may be used in bone tissue engineering applications, are insulin-like growth factor-1, 145 hepatocyte growth factor, 146 sphingosine 1-phosphate 147 and its receptor agonist FTY720, 148,149 angiopoietin-2, 150 plasma factor XIII, 151 G-CSF, 84 the glycoprotein fibrinogen, 152 and PRP, which contains a variety of cytokines (i.e., platelet-derived growth factor, TGF-b, and epidermal growth factor). [153][154][155][156] Of note, the local application of clinically approved drugs at the bone defect site, such as simvastatin, 157,158 rosuvastatin, 159 desferrioxamine, [160][161][162][163] and even antibiotics like minocycline, 164 has also beneficial effects on vascularization and bone formation.…”

Section: Local Growth Factor-based Vascularization Strategiesmentioning

confidence: 99%

Vascularization Strategies in the Prevention of Nonunion Formation

Menger

Laschke

Orth

et al. 2021

Tissue Engineering Part B: Reviews

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Delayed healing and nonunion formation are major challenges in orthopedic surgery, which require the development of novel treatment strategies. Vascularization is considered one of the major prerequisites for successful bone healing, providing an adequate nutrient supply and allowing the infiltration of progenitor cells to the fracture site. Hence, during the last decade, a considerable number of studies have focused on the evaluation of vascularization strategies to prevent or to treat nonunion formation. These involve (1) biophysical applications, (2) systemic pharmacological interventions, and (3) tissue engineering, including sophisticated scaffold materials, local growth factor delivery systems, cell-based techniques, and surgical vascularization approaches. Accumulating evidence indicates that in nonunions, these strategies are indeed capable of improving the process of bone healing. The major challenge for the future will now be the translation of these strategies into clinical practice to make them accessible for the majority of patients. If this succeeds, these vascularization strategies may markedly reduce the incidence of nonunion formation.

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The Effects of Desferroxamine on Bone and Bone Graft Healing in Critical-Size Bone Defects

Cited by 8 publications

References 28 publications

Intraperitoneal injection of Desferal® alleviated the age-related bone loss and senescence of bone marrow stromal cells in rats

Intraperitoneal injection of Desferal® alleviated the age-related bone loss and senescence of bone marrow stromal cells in rats

Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering

Vascularization Strategies in the Prevention of Nonunion Formation

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