title: Long-term administration of AMD3100, an antagonist of SDF-1/CXCR4 signaling, alters fracture repair.
abstract: Fracture healing involves rapid stem and progenitor cell migration, homing, and differentiation. SDF-1 (CXCL12) is considered a master regulator of CXCR4-positive stem and progenitor cell trafficking to sites of ischemic (hypoxic) injury and regulates their subsequent differentiation into mature reparative cells. In this study, we investigated the role of SDF-1/CXCR4 signaling in fracture healing where vascular disruption results in hypoxia and SDF-1 expression. Mice were injected with AMD3100, a CXCR4 antagonist, or vehicle twice daily until euthanasia with the intent to impair stem cell homing to the fracture site and/or their differentiation. Fracture healing was evaluated using micro-computed tomography, histology, quantitative PCR, and mechanical testing. AMD3100 administration resulted in a significantly reduced hyaline cartilage volume (day 14), callus volume (day 42) and mineralized bone volume (day 42) and reduced expression of genes associated with endochondral ossification including collagen Type 1 alpha 1, collagen Type 2 alpha 1, vascular endothelial growth factor, Annexin A5, nitric oxide synthase 2, and mechanistic target of rapamycin. Our data suggest that the SDF-1/CXCR4 signaling plays a central role in bone healing possibly by regulating the recruitment and/or differentiation of stem and progenitor cells.
authors.affiliation: Department of Anatomy, Physiology, and Cell Biology, Davis, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Chrisoula A
authors.initials: CA
authors.lastname: Toupadakis
authors.forename: Alice
authors.initials: A
authors.lastname: Wong
authors.forename: Damian C
authors.initials: DC
authors.lastname: Genetos
authors.forename: Dai-Jung
authors.initials: DJ
authors.lastname: Chung
authors.forename: Deepa
authors.initials: D
authors.lastname: Murugesh
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Anderson
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
authors.forename: Blaine A
authors.initials: BA
authors.lastname: Christiansen
authors.forename: Amy S
authors.initials: AS
authors.lastname: Kapatkin
authors.forename: Clare E
authors.initials: CE
authors.lastname: Yellowley
mesh_terms: D000818:Animals; D001596:Benzylamines; D001696:Biomechanical Phenomena; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D017102:Fracture Healing; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis; D016133:Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor