Sildenafil accelerates fracture healing in mice

Authors

  • Tina Histing,

    Corresponding author
    1. Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
    2. CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany
    • Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D-66421 Homburg/Saar, Germany, T: 49-6841-16-31502; F: 49-6841-16-31503.
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  • Kerstin Marciniak,

    1. Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
    2. CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany
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  • Claudia Scheuer,

    1. CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany
    2. Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany
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  • Patric Garcia,

    1. Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
    2. CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany
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  • Joerg H. Holstein,

    1. Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
    2. CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany
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  • Moritz Klein,

    1. Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
    2. CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany
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  • Romano Matthys,

    1. AO Development Institute, Davos, Switzerland
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  • Tim Pohlemann,

    1. Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
    2. CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany
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  • Michael D. Menger

    1. CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany
    2. Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany
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Abstract

Sildenafil, a cyclic guanosine monophosphate (cGMP)-dependent phospodiesterase-5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro-angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro-angiogenic and osteogenic cysteine-rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61-associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873

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