CXCR4 Antagonism to Treat Delayed Fracture Healing

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.Impact StatementCurrently ∼10% of fractures progress to delayed or nonunion with significant morbidity and economic impact. Endogenous mobilization of stem cells by pharmacological antagonism of their homing and migration receptor CXCR4 with AMD3100 experimentally reduced delayed union development. Endogenous mobilization may, therefore, translate as a low risk means to boost healing and could potentially be given as a prophylaxis to patients with fractures at risk of delayed healing or nonunion. These patients may include fragility fractures, comminuted tibial fractures, or when treating established nonunions. This approach could have promise for other conditions that may benefit from stem cell treatments.

Effectiveness of granulocyte colony stimulating factor to enhance healing on delayed union fracture model Sprague-Dawley rat

“…The results obtained were different from the research conducted by Meeson R et al on Wistar rats. In this study, an increase in the percentage of cartilage formation in the treatment group with a combination of G-CSF and the antagonist CXCR4 [ 36 ]. Research conducted by Herrmann et al also showed similar results, where there was an increase in the formation of cartilage areas in the G-CSF treatment compared to controls [ 28 ].…”