title: Local delivery of iron chelators reduces in vivo remodeling of a calcium phosphate bone graft substitute.
abstract: Iron chelators are known activators of the Hypoxia Includible Factor-1α (HIF-1α) pathway, a critical cellular pathway involved in angiogenic responses to hypoxia. Local delivery of these chelators has shown promise in bone tissue engineering strategies by inducing angiogenesis and osteogenesis. Hypoxic microenvironments are also a stimulus for osteoclast differentiation and resorptive activity, a process likely mediated by HIF-1α. In vitro, low doses of the iron chelator Deferoxamine (DFO) has shown to induce HIF-1α mediated osteoclast formation and function. However other studies have proposed an opposite in vitro effect likely through HIF independent mechanisms. To investigate use of these medications in bioceramic based bone tissue engineering strategies this study aimed to determine the in vivo effect of local delivery of iron chelators on bioceramic remodeling. A non-weight bearing cranial onlay model was used to assess monetite resorption and new bone formation in the presence or absence of a repeated delivery of two iron chelators, DFO and 1,10 Phenanthroline (PHT) at doses known to induce HIF. We found a marked reduction graft resorption and remodeling associated with iron chelation. This was correlated to a 3-fold reduction in osteoclast number at the bone graft interface. Iron is needed for mitochondrial biogenesis during osteoclastic differentiation and reducing extracellular iron levels may inhibit this process and possibly overpower any HIF induced osteoclast formation. Our findings suggest that these inexpensive and widely available molecules may be used to locally reduce bioceramic scaffold resorption and encourages future investigations of iron chelators as bone anti-resorptive agents in other clinical contexts.
  
  
  
  Low doses of iron chelators can induce angiogenesis and osteogenesis in repairing bone by stimulating the oxygen sensitive gene; hypoxia inducible factor. These medications have potential to augment bioceramic based bone tissue engineering strategies without the downsides of protein-based growth factors. HIF activation is also known to stimulate osteoclast-mediated resorption and could potentially accelerate remodeling of biocermaics, however we have shown that the local delivery of iron chelation at doses known to induce HIF resulted in a reduction of monetite resorption and a significant decrease in osteoclast number at the bone graft interface. This maybe due to HIF independent mechanism. This is the first study to show a local effect of iron chelators in vivo on osteoclast-mediated resorption. This opens the potential of further study of these bifunctional medications to modulate resorption of biocermaics in environments where a prolonged presence of material is desired for graft site stability. Moreover these safe widely used medications can be explored to locally reduce osteoclasts in pathological bone resorption.
authors.affiliation: Division of Orthopaedics, McGill University Health Center, 1650 Cedar Ave, Montreal, Qc H3G 1A4, Canada. Electronic address: Justin.drager@mail.mcgill.ca.
authors.forename: Justin
authors.initials: J
authors.lastname: Drager
authors.affiliation: Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON M5S 3E2, Canada. Electronic address: Zeeshan.sheikh@utoronto.ca.
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Sheikh
authors.affiliation: Division of Orthopaedics, McGill University Health Center, 1650 Cedar Ave, Montreal, Qc H3G 1A4, Canada; Faculty of Dentistry, McGill University, 3640, Rue University, Montreal, Qc H3A 0C7, Canada. Electronic address: Yu.l.zhang@mcgill.ca.
authors.forename: Yu Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Division of Orthopaedics, McGill University Health Center, 1650 Cedar Ave, Montreal, Qc H3G 1A4, Canada. Electronic address: Edward.harvey@mcgill.ca.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Harvey
authors.affiliation: Division of Orthopaedics, McGill University Health Center, 1650 Cedar Ave, Montreal, Qc H3G 1A4, Canada; Faculty of Dentistry, McGill University, 3640, Rue University, Montreal, Qc H3A 0C7, Canada. Electronic address: jake.barralet@mcgill.ca.
authors.forename: Jake E
authors.initials: JE
authors.lastname: Barralet
mesh_terms: D000818:Animals; D018786:Bone Substitutes / Q000494:pharmacology*; D016025:Bone Transplantation; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery; D002130:Calcium Phosphates / Q000494:pharmacology*; D016503:Drug Delivery Systems; D021621:Imaging, Three-Dimensional; D020007:Implants, Experimental; D007430:Intraoperative Care; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D011817:Rabbits; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D014961:X-Ray Diffraction
chemical_list: D018786:Bone Substitutes; D002130:Calcium Phosphates; D007502:Iron Chelating Agents; C020243:calcium phosphate; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Bioceramic bone graft; Deferoxamine (DFO); Hypoxia Inducible Factor; Hypoxia mimic; Iron chelator; Osteoclast; Resorption