CXCR4 antagonism to treat delayed fracture healing

Richard Meeson, Anita Sanghani-Keri, Melanie Coathup, Gordon Blunn

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    Abstract

    A significant number of fractures develop nonunion. Stem cell homing is regulated through stromal cell-derived factor 1 (SDF1) and its receptor CXCR4. Stem/progenitor cell populations can be endogenously mobilized by administering growth factors with a pharmacological antagonist of CXCR4, AMD3100, which may be a means to improve fracture healing. A 1.5 mm femoral osteotomy in Wistar rats was stabilized with an external fixator. Rats were pretreated with phosphate buffered saline [PBS(P)], vascular endothelial growth factor [VEGF(V)], insulin-like growth factor-1 [IGF1(I)], or granulocyte colony stimulating factor [GCSF(G)] before AMD3100. A control group (C) did not receive growth factors or AMD3100. Bone formation after 5 weeks was analyzed. Group P had a significant increase in total bone volume (BV) (p = 0.01) and group I in percentage bone in the fracture gap (p = 0.035). Group G showed a decrease in BV. All treated groups had an increase in trabecular thickness. Histology showed decreased cartilage tissue associated with increased bone in groups with improved healing, and increased fibrous tissue in poorly performing groups. Antagonism of SDF1-CXCR4 axis can boost impaired fracture healing. AMD3100 given alone was the most effective means to boost healing, whereas pretreatment with GCSF reduced healing. AMD3100 is likely mobilizing stem cells into the blood stream that home to the fracture site enhancing healing.
    Original languageEnglish
    Pages (from-to)1242-1250
    Number of pages9
    JournalTissue Engineering - Part A
    Volume25
    Issue number17-18
    Early online date14 Jun 2019
    DOIs
    Publication statusPublished - 17 Sept 2019

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