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ABSTRACT: ABSTRACT Background: Osteoporosis is characterized by poor bone quality. However, it is still controversially discussed whether osteoporosis compromises fracture healing. Herein, we studied whether the course of healing of a femur fracture is affected by osteoporosis or age. Methods: Using the senescence-accelerated osteoporotic mouse, strain P6 (SAMP6), and a closed femur fracture model, we studied the process of fracture healing in 5- and 10-month-old animals, including biomechanical, histomorphometric, and protein biochemical analysis. Results: In five-month-old osteoporotic SAMP6 mice, bending stiffness, callus size, and callus tissue distribution as well as the concentrations of the bone formation marker osteocalcin and the bone resorption markers tartrate-resistant acid phosphatase form 5b (TRAP) and deoxypyridinoline (DPD) did not differ from that of non-osteoporotic, senescence-resistant, strain 1 (SAMR1) controls. In contrast, femur fractures in 10-month-old SAMP6 mice showed a significantly reduced bending stiffness and an increased callus size compared to fractures in age-matched SAMR1 controls. This indicates a delayed fracture healing in advanced age SAMP6 mice. The delay of fracture healing was associated with higher concentrations of TRAP and DPD. Significant differences in osteocalcin concentrations were not found between SAMP6 animals and SAMR1 controls. Conclusion: In conclusion, the present study indicates that fracture healing in osteoporotic SAMP6 mice is not affected in five-month-old animals, but delayed in animals with an age of 10 months. This is most probably due to the increased osteoclast activity in advanced age SAMP6 animals.
Journal of Investigative Surgery 12/2012; · 1.09 Impact Factor
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ABSTRACT: BACKGROUND: Despite the increasing clinical problems with metaphyseal fractures, most experimental studies investigate the healing of diaphyseal fractures. Although the mouse would be the preferable species to study the molecular and genetic aspects of metaphyseal fracture healing, a murine model does not exist yet. Using a special locking plate system, we herein introduce a new model, which allows the analysis of metaphyseal bone healing in mice. METHODS: In 24 CD-1 mice the distal metaphysis of the femur was osteotomized. After stabilization with the locking plate, bone repair was analyzed radiologically, biomechanically, and histologically after 2 (n=12) and 5wk (n=12). Additionally, the stiffness of the bone-implant construct was tested biomechanically ex vivo. RESULTS: The torsional stiffness of the bone-implant construct was low compared with nonfractured control femora (0.23±0.1Nmm/°versus 1.78±0.15Nmm/°, P<0.05). The cause of failure was a pullout of the distal screw. At 2wk after stabilization, radiological analysis showed that most bones were partly bridged. At 5wk, all bones showed radiological union. Accordingly, biomechanical analyses revealed a significantly higher torsional stiffness after 5wk compared with that after 2wk. Successful healing was indicated by a torsional stiffness of 90% of the contralateral control femora. Histological analyses showed new woven bone bridging the osteotomy without external callus formation and in absence of any cartilaginous tissue, indicating intramembranous healing. CONCLUSION: With the model introduced herein we report, for the first time, successful metaphyseal bone repair in mice. The model may be used to obtain deeper insights into the molecular mechanisms of metaphyseal fracture healing.
Journal of Surgical Research 04/2012; · 2.25 Impact Factor
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ABSTRACT: Reproductive isolation among locally adapted populations may arise when immigrants from foreign habitats are selected against via natural or (inter-)sexual selection (female mate choice). We asked whether also intrasexual selection through male-male competition could promote reproductive isolation among populations of poeciliid fishes that are locally adapted to extreme environmental conditions [i.e., darkness in caves and/or toxic hydrogen sulphide (H(2)S)]. We found strongly reduced aggressiveness in extremophile P. oecilia mexicana, and darkness was the best predictor for the evolutionary reduction of aggressiveness, especially when combined with presence of H(2)S. We demonstrate that reduced aggression directly translates into migrant males being inferior when paired with males from non-sulphidic surface habitats. By contrast, the phylogenetically old sulphur endemic P. sulphuraria from another sulphide spring area showed no overall reduced aggressiveness, possibly indicating evolved mechanisms to better cope with H(2)S.
International journal of evolutionary biology. 01/2012; 2012:148745.
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ABSTRACT: Fragility fractures represent one of the major problems associated with osteoporosis. While in the mid-1990s about half a
million hospital admissions in the United States were due to osteoporotic fractures, this number will triple until 2040. Of
interest, already in 1995, the direct costs produced by osteoporotic fractures were more than US$14 billion, whereas the indirect
costs are estimated to be up to five times higher.
05/2011: pages 175-191;
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Joerg H Holstein,
Markus Herrmann,
Christina Splett,
Wolfgang Herrmann,
Patric Garcia,
Tina Histing, Moritz Klein,
Karsten Kurz,
Thomas Siebel,
Tim Pohlemann,
Michael D Menger
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ABSTRACT: Accumulation of homocysteine and S-adenosylhomocysteine in bone has been shown to be associated with reduced bone quality in rats. The aim of the present study was to investigate whether high bone concentrations of homocysteine and S-adenosylhomocysteine as well as a low methylation capacity are related to an impaired bone morphology in humans. Concentrations of homocysteine and its precursors S-adenosylhomocysteine and S-adenosylmethionine were measured in femoral bone samples of eighty-two males and females (age 71 (SD 8) years) who underwent elective hip arthroplasty. Cancellous bone structure was analysed by histomorphometry. In addition, blood was sampled to measure serum concentrations of homocysteine. Results of bone and serum analyses were grouped for individuals with high or low bone concentrations of homocysteine, S-adenosylhomocysteine and S-adenosylmethionine, as well as for individuals with a high or a low methylation capacity, which is indicated by a low or a high S-adenosylhomocysteine:S-adenosylmethionine ratio (n 41, each). Histomorphometry showed a higher trabecular separation and a lower trabecular thickness, trabecular number and trabecular area in individuals with high bone concentrations of homocysteine and S-adenosylhomocysteine compared with individuals with low bone concentrations of homocysteine and S-adenosylhomocysteine. There was no association between the S-adenosylhomocysteine:S-adenosylmethionine ratio and bone morphology. It was found that 48 % of bone homocysteine was bound to the collagen of the extracellular bone matrix. Blood analyses demonstrated a significant correlation between serum and bone homocysteine. The results of the present study indicate an association between altered bone morphology and elevated bone concentrations of homocysteine and S-adenosylhomocysteine, but not between altered bone morphology and methylation capacity.
The British journal of nutrition 04/2011; 106(3):378-82. · 3.45 Impact Factor
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ABSTRACT: 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.
Therefore, we herein studied fracture healing in female and male senescence-accelerated osteoporotic mice, strain P6 (SAMP6), including biomechanical, histomorphometric, and protein biochemical analysis.
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.
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.
Journal of Surgical Research 04/2011; 175(2):271-7. · 2.25 Impact Factor
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David Bierbach,
Antje Girndt,
Sybille Hamfler, Moritz Klein,
Frauke Mücksch,
Marina Penshorn,
Michael Schwinn,
Claudia Zimmer,
Ingo Schlupp,
Bruno Streit,
Martin Plath
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ABSTRACT: Mate choice as one element of sexual selection can be sensitive to public information from neighbouring individuals. Here, we demonstrate that males of the livebearing fish Poecilia mexicana gather complex social information when given a chance to familiarize themselves with rivals prior to mate choice. Focal males ceased to show mating preferences when being observed by a rival (which prevents rivals from copying mating decisions), but this effect was only seen when focal males have perceived rivals as sexually active. In addition, focal males that were observed by a familiar, sexually active rival showed a stronger behavioural response when rivals were larger and thus, more attractive to females. Our study illustrates an unparalleled adjustment in the expression of mating preferences based on social cues, and suggests that male fish are able to remember and strategically exploit information about rivals when performing mate choice.
Biology letters 01/2011; 7(3):349-51. · 3.76 Impact Factor
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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.
Journal of Orthopaedic Research 01/2011; 29(6):867-73. · 2.81 Impact Factor
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ABSTRACT: The aim of the present study was to investigate the effect of exercise on angiogenesis during bone defect healing in mice. We evaluated angiogenesis during cranial bone defect healing by intravital fluorescence microscopy (IVM) at days 0-21. To characterize the type of bone repair, we performed additional histomorphometric analyses at days 3-15. IVM was conducted in mice, which were housed in cages supplied with running wheels (exercise group; n=7) and compared to IVM results of mice, which were housed in cages without running wheels (controls; n=7). In the exercise group, we additionally performed correlation analyses between results of the IVM and the running distance. IVM showed an accelerated decrease of bone defect area in the exercise group compared to the control group. This was associated with a significantly higher blood vessel diameter in animals undergoing exercise at days 9 and 12 and a significant correlation between running distance and blood vessel density at day 9 (r = 0.74). Histomorphometry showed osseous bridging of the defect at day 9. The newly woven bone was covered by a neo-periosteum containing those blood vessels, which were visible by IVM. We conclude that exercise accelerates bone defect healing and stimulates angiogenesis during bore repair.
Journal of Orthopaedic Research 01/2011; 29(7):1086-92. · 2.81 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Journal of Surgical Research 09/2010; 173(1):83-90. · 2.25 Impact Factor
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Joerg H Holstein,
Markus Herrmann,
Christina Splett,
Wolfgang Herrmann,
Patric Garcia,
Tina Histing, Moritz Klein,
Karsten Kurz,
Thomas Siebel,
Tim Pohlemann,
Michael D Menger
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ABSTRACT: Recent clinical and animal studies suggest that increased serum homocysteine (HCY) concentrations may be a risk factor for osteoporosis. In vitro studies showed that increasing HCY concentrations stimulate the activity of human osteoclasts. However, there is no data demonstrating that circulating HCY is related to structural and biomechanical properties of human bones. This study investigated the relationship between morphological as well as biomechanical bone properties and HCY serum concentrations in humans suffering from hip osteoarthritis (OA).
Fasting blood samples and femoral heads were obtained from 94 males and females who underwent hip arthroplasty due to OA. Bones were assessed by dual energy X-ray absorptiometry (DXA), biomechanical testing (indentation method), and histomorphometry. Blood was collected for measurement of HCY, folate, vitamin B6, and vitamin B12. Subjects were classified as hyperhomocysteinemic (>12 micromol/L, n=47) and normohomocysteinemic (<12 micromol/L, n=47) according to their serum HCY concentrations.
Folate and vitamin B6, but not vitamin B12, were significantly lower in hyperhomocysteinemic subjects compared with controls. However, DXA, biomechanical testing, and histomorphometry did not reveal significant differences in bone quality between hyperhomocysteinemic subjects and controls.
The results of the present study do not indicate a significant relationship between circulating HCY concentrations and morphological or biomechanical bone properties in humans with OA of the hip.
Clinical Chemistry and Laboratory Medicine 03/2010; 48(6):821-7. · 2.15 Impact Factor
