Sildenafil accelerates fracture healing in mice.
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.
Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, Homburg/Saar, Germany. tina.histing@uks.eu
Tina
T
Histing
Kerstin
K
Marciniak
Claudia
C
Scheuer
Patric
P
Garcia
Joerg H
JH
Holstein
Moritz
M
Klein
Romano
R
Matthys
Tim
T
Pohlemann
Michael D
MD
Menger
D000818:Animals; D001696:Biomechanical Phenomena; D015153:Blotting, Western; D004353:Drug Evaluation, Preclinical; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005269:Femur / Q000473:pathology; D017102:Fracture Healing / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D011859:Radiography; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
D036341:Intercellular Signaling Peptides and Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate