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Histing T.,Saarland University | Histing T.,Homburg Collaborative Research Center | Marciniak K.,Saarland University | Marciniak K.,Homburg Collaborative Research Center | And 13 more authors.
Journal of Orthopaedic Research | Year: 2011

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. Source


Histing T.,Saarland University | Histing T.,Homburg Collaborative Research Center | Anton C.,Saarland University | Anton C.,Homburg Collaborative Research Center | And 13 more authors.
Journal of Surgical Research | Year: 2012

Background: Melatonin, the major pineal hormone, is known to regulate distinct physiologic processes. Previous studies have suggested that it supports skeletal growth and bone formation, most probably by inhibiting bone resorption. There is no information, however, whether melatonin affects fracture healing. We therefore studied in a mouse femur fracture model the influence of melatonin on callus formation and biomechanics during fracture healing. Methods and Materials: Thirty CD-1 mice received 50 mg/kg body weight melatonin i.p. daily during the entire 2-wk or 5-wk observation period. Controls (n = 30) received equivalent amounts of vehicle. Bone healing was studied by radiological, biomechanical, histomorphometrical, and protein biochemical analyses at 2 and 5 wk after fracture. Results: Biomechanical analysis at 2 wk after fracture healing showed a significantly lower bending stiffness in melatonin-treated animals compared with controls. A slightly higher amount of cartilage tissue and a significantly larger callus size indicated a delayed remodeling process after melatonin treatment. Western blot analysis showed a significantly reduced expression of receptor activator of nuclear factor-κB ligand (RANKL) and collagen I after melatonin treatment. The reduced expression of RANKL was associated with a diminished number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts within the callus of the newly formed bone. Conclusions: Because bone resorption is an essential requirement for adequate remodeling during fracture healing, we conclude that melatonin impairs fracture healing by suppressing bone resorption through down-regulation of RANKL-mediated osteoclast activation. © 2012 Elsevier Inc. All rights reserved. Source


Histing T.,Saarland University | Histing T.,Homburg Collaborative Research Center | Garcia P.,Saarland University | Garcia P.,Homburg Collaborative Research Center | And 24 more authors.
Bone | Year: 2011

Small animal fracture models have gained increasing interest in fracture healing studies. To achieve standardized and defined study conditions, various variables must be carefully controlled when designing fracture healing experiments in mice or rats. The strain, age and sex of the animals may influence the process of fracture healing. Furthermore, the choice of the fracture fixation technique depends on the questions addressed, whereby intra- and extramedullary implants as well as open and closed surgical approaches may be considered. During the last few years, a variety of different, highly sophisticated implants for fracture fixation in small animals have been developed. Rigid fixation with locking plates or external fixators results in predominantly intramembranous healing in both mice and rats. Locking plates, external fixators, intramedullary screws, the locking nail and the pin-clip device allow different degrees of stability resulting in various amounts of endochondral and intramembranous healing. The use of common pins that do not provide rotational and axial stability during fracture stabilization should be discouraged in the future. Analyses should include at least biomechanical and histological evaluations, even if the focus of the study is directed towards the elucidation of molecular mechanisms of fracture healing using the largely available spectrum of antibodies and gene-targeted animals to study molecular mechanisms of fracture healing. This review discusses distinct requirements for the experimental setups as well as the advantages and pitfalls of the different fixation techniques in rats and mice. © 2011 Elsevier Inc. Source


Histing T.,Saarland University | Histing T.,Homburg Collaborative Research Center | Stenger D.,Saarland University | Stenger D.,Homburg Collaborative Research Center | And 15 more authors.
Journal of Surgical Research | Year: 2012

Background: Previous studies have shown that fracture healing depends on gender and that in females, ovariectomy-induced osteoporosis impairs the healing process. There is no information, however, whether the alteration of fracture healing in osteoporosis also depends on gender. Materials and Methods: Therefore, we herein studied fracture healing in female and male senescence-accelerated osteoporotic mice, strain P6 (SAMP6), including biomechanical, histomorphometric, and protein biochemical analysis. Results: Bending stiffness was reduced in male and female SAMP6 mice compared with senescence-resistant strain 1 (SAMR1) controls. This was associated with elevated serum concentrations of tartrate-resistent acid phosphatase form 5b (TRAP) in both female and male SAMP6 mice. Callus size, however, was significantly larger in female SAMP6 mice compared with male SAMP6 mice and female SAMR1 controls. This indicates a delayed remodeling process in female SAMP6 mice. The delay of callus remodeling in female SAMP6 mice was associated with a significantly higher osteoprotegerin (OPG) callus tissue expression and increased serum concentrations of osteocalcin (OC) and deoxypyridinoline (DPD), indicating elevated osteoblast and osteoclast activities. Conclusion: The present study shows that remodeling during fracture healing in female, but not in male, SAMP6 mice is delayed, most probably due to an increased osteoblast and osteoclast activity. © 2012 Elsevier Inc. All rights reserved. Source


Histing T.,Saarland University | Histing T.,Homburg Collaborative Research Center | Stenger D.,Saarland University | Stenger D.,Homburg Collaborative Research Center | And 14 more authors.
Calcified Tissue International | Year: 2012

Proton pump inhibitors (PPIs), which are widely used in the treatment of dyspeptic problems, have been shown to reduce osteoclast activity. There is no information, however, on whether PPIs affect fracture healing. We therefore studied the effect of the PPI pantoprazole on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analyses at 2 and 5 weeks after fracture. Twenty-one mice received 100 mg/kg body weight pantoprazole i.p. daily. Controls (n = 21) received equivalent amounts of vehicle. In pantoprazole-treated animals biomechanical analysis revealed a significantly reduced bending stiffness at 5 weeks after fracture compared to controls. This was associated with a significantly lower amount of bony tissue within the callus and higher amounts of cartilaginous and fibrous tissue. Western blot analysis showed reduced expression of the bone formation markers bone morphogenetic protein (BMP)-2, BMP-4, and cysteine-rich protein (CYR61). In addition, significantly lower expression of proliferating cell nuclear antigen indicated reduced cell proliferation after pantoprazole treatment. Of interest, the reduced expression of bone formation markers was associated with a significantly diminished expression of RANKL, indicating osteoclast inhibition. Pantoprazole delays fracture healing by affecting both bone formation and bone remodeling. © Springer Science+Business Media, LLC 2012. Source

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