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Rapamycin affects early fracture healing in mice
Author(s) -
Holstein J H,
Klein M,
Garcia P,
Histing T,
Culemann U,
Pizanis A,
Laschke M W,
Scheuer C,
Meier C,
Schorr H,
Pohlemann T,
Menger M D
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.167
Subject(s) - bone healing , angiogenesis , sirolimus , callus , medicine , neovascularization , transplantation , vascular endothelial growth factor , femur fracture , cancer research , surgery , femur , biology , vegf receptors , genetics
Background and purpose: The immunosuppressive drug rapamycin (RAPA) prevents rejection in organ transplantation by inhibiting interleukin‐2‐stimulated T‐cell division. Rapamycin has also been suggested to possess strong anti‐angiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF). Angiogenesis and VEGF are thought to play a crucial role in fracture healing and as osteoporotic and traumatic fractures are common complications in immunosuppressed, organ transplantation patients, we conducted this study to analyze the effect of rapamycin treatment on bone repair. Experimental approach: We investigated the effect of rapamycin treatment on bone repair in a murine closed femur fracture model using radiological, histomorphometric, immunohistochemical, biomechanical and protein biochemical analyses. Key results: X‐ray analyses demonstrated that rapamycin treatment inhibits callus formation after two weeks of fracture healing. The radiologically observed lack of callus formation was confirmed by histomorphometric analyses, which revealed a significantly diminished callus size and a reduced amount of bone formation when compared with vehicle‐treated controls. Biomechanical testing further demonstrated that rapamycin significantly reduces torsional stiffness of the callus. Interestingly, this effect was associated with decreased vessel formation; a diminished proliferation of osteoblasts, endothelial cells and periosteal cells; and a reduced VEGF expression in hypertrophic chondrocytes. After five weeks treatment, however, the negative impact of rapamycin on fracture healing was overcome. Conclusions and implications: Thus, rapamycin initially delays fracture healing, most probably by inhibiting cell proliferation and neovascularization in the callus. These undesirable effects should be considered when rapamycin is administered to patients sustaining bone fractures. British Journal of Pharmacology (2008) 154 , 1055–1062; doi: 10.1038/bjp.2008.167 ; published online 5 May 2008