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Despite the growing knowledge on the mechanisms of fracture healing, delayed healing and non-union formation remain a major clinical challenge. Animal models are needed to study the complex process of normal and impaired fracture healing and to develop new therapeutic strategies. Whereas in the past mainly large animals have been used to study normal and impaired fracture healing, nowadays rodent models are of increasing interest. New osteosynthesis techniques for rat and mice have been developed during the last years, which allowed for the first time stable osteosynthesis in these animals comparable to the standards in large animals and humans. Based on these new implants, different models in rat and mice have been established to study delayed healing and non-union formation. Although in humans the terms delayed union and non-union are well defined, in rodents definitions are lacking. However, especially in scientific studies clear definitions are necessary to develop a uniform scientific language and allow comparison of the results between different studies. In this consensus report, we define the basic terms "union", "delayed healing" and "non-union" in rodent animal models. Based on a review of the literature and our own experience, we further provide an overview on available models of delayed healing and non-union formation in rats and mice. We further summarise the value of different approaches to study normal and delayed fracture healing as well as non-union formation, and discuss different methods of data evaluation.

The availability of a broad spectrum of antibodies and gene-targeted animals caused an increasing interest in mouse models for the study of molecular mechanisms of fracture healing and bone regeneration. In most murine fracture models, the tibia or the femur is fractured using a 3-point bending device (closed models) or is osteotomized using an open surgical approach (open models). For fracture studies in mice, the tibia has to be considered less appropriate compared with the femur because the stabilization of the fracture is more difficult due to its triangular, distally declining caliber and its bowed longitudinal axis. Biomechanical factors critically influence the bone healing process. Thus, the use of stable osteosynthesis techniques is also of interest in murine fracture models. To achieve stable fixation, several biomechanically standardized implants have recently been introduced, including a locking nail and an intramedullary compression screw. Other implants, such as a pin-clip, an external fixator, and a locking plate, additionally allow the stabilization of fractures with distinct gap sizes. This enables the study of healing of critical size defects and nonunions. The use of these implants further allows a rigid fixation of fractures in bridle bones, which is essential for fracture studies in animals suffering from metabolic bone diseases like osteoporosis. In general, the analysis of bone healing in these models includes different imaging techniques and histologic, immunohistochemical, biomechanical, and molecular methods. To evaluate the impact of different osteosynthesis techniques on physical activity and rehabilitation, gait analysis may additionally be performed. By this, the gait of the animals can be visualized and quantitatively analyzed using modified running wheels and dynamic high-resolution radiography systems. Taken together, a variety of different murine femur fracture models have become available, providing defined biomechanical conditions for fracture research. The use of these mouse models may now allow studying the influence of fracture stabilization techniques on molecular mechanisms of bone healing.

Morbus Ledderhose is a rare hyperproliferative disease of the plantar fascia, leading to the formation of nodules. Its origin is unknown. No causal therapy is available, and treatment remains symptomatic. Various therapeutic strategies to alleviate symptoms are available and are adapted to the severity of the disease. In early stages, conservative therapy including nonpharmacological, physical, and pharmacological treatments is applied. If the disease progresses, irradiation of the plantar surface, injections of steroids, shock wave therapy, and partial or complete fasciectomy as an ultimate therapy may be indicated. Novel experimental treatment options including application of fibrinolytic agents are currently being tested, but no controlled, randomized long-term studies are available. This review aims to provide a systematic overview of current established procedures and outlines novel experimental strategies for the treatment of morbus Ledderhose, including future avenues to treat this rare disease.

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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 ¼ 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. ß

Background and purpose:The renin-angiotensin system (RAS) regulates blood pressure and electrolyte homeostasis. In addition, 'local' tissue-specific RAS have been identified, regulating regeneration, cell growth, apoptosis, inflammation and angiogenesis. Although components of the RAS are expressed in osteoblasts and osteoclasts, a local RAS in bone has not yet been described and there is no information on whether the RAS is involved in fracture healing. Therefore, we studied the expression and function of the key RAS component, angiotensin-converting enzyme (ACE), during fracture healing. Experimental approach: In a murine femur fracture model, animals were treated with the ACE inhibitor perindopril or vehicle only. Fracture healing was analysed after 2, 5 and 10 weeks using X-ray, micro-CT, histomorphometry, immunohistochemistry, Western blotting and biomechanical testing. Key results: ACE was expressed in osteoblasts and hypertrophic chondrocytes in the periosteal callus during fracture healing, accompanied by expression of the angiotensin type-1 and type-2 receptors. Perindopril treatment reduced blood pressure and bone mineral density in unfractured femora. However, it improved periosteal callus formation, bone bridging of the fracture gap and torsional stiffness. ACE inhibition did not affect cell proliferation, but reduced apoptotic cell death. After 10 week treatment, a smaller callus diameter and bone volume after perindopril treatment indicated an advanced stage of bone remodelling. Conclusions: Our study provides evidence for a local RAS in bone that influenced the process of fracture healing. We show for the first time that inhibition of ACE is capable of accelerating bone healing and remodelling.