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      Traumatic brain injury and bone healing: radiographic and biomechanical analyses of bone formation and stability in a combined murine trauma model

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          Abstract

          Introduction:

          The combination of traumatic brain injury (TBI) and long-bone fractures has previously been reported to lead to exuberant callus formation. The aim of this experimental study was to radiographically and biomechanically study the effect of TBI on bone healing in a mouse model.

          Materials and methods:

          138 female C57/Black6N mice were assigned to four groups (fracture (Fx) / TBI / combined trauma (Fx/TBI) / controls). Femoral osteotomy and TBI served as variables: osteotomies were stabilized with external fixators, TBI was induced with controlled cortical impact injury. During an observation period of four weeks, in vivo micro-CT scans of femora were performed on a weekly basis. Biomechanical testing of femora was performed ex vivo.

          Results:

          The combined-trauma group showed increased bone volume, higher mineral density, and a higher rate of gap bridging compared to the fracture group. The combined-trauma group showed increased torsional strength at four weeks.

          Discussion:

          TBI results in an increased formation of callus and mineral density compared to normal bone healing in mice. This fact combined with a tendency towards accelerated gap bridging leads to increased torsional strength. The present study underscores the empirical clinical evidence that TBI stimulates bone healing. Identification of underlying pathways could lead to new strategies for bone-stimulating approaches in fracture care.

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          Most cited references24

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          Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass.

          Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.
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            A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure.

            Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.
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              A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects.

              Controlled cortical impact (CCI), using a pneumatically driven impactor to produce traumatic brain injury, has been characterized previously in both the ferret and in the rat. In the present study, we applied this technique to establish and characterize the CCI model of brain injury in another species, the mouse, evaluating cognitive and histopathologic outcome. In anesthetized (sodium pentobarbital, 65 mg/kg) male C57BL mice, we performed sham treatment (no injury, n = 12) or CCI injury (n = 12) at a velocity of 5.7-6.2 m/sec and depth of 1 mm, using a 3-mm diameter rounded-tip impounder, positioned over the left parietotemporal cortex (parasagittal). At this level of injury, we observed highly significant deficits in memory retention of a Morris water maze task 2 days following injury (p < 0.001). Postmortem histopathologic analysis performed at 48 h following injury revealed substantial cortical tissue loss in the region of impact and selective hippocampal neuronal cell loss in the CA2, CA3, and CA3c regions, using Nissl staining. Analysis of degenerating neurons using modified Gallyas silver staining techniques demonstrated consistent ipsilateral injury of neurons in the cortex adjacent to the impact site and in the dentate gyrus of the ipsilateral hippocampus. Bilateral degeneration was observed at the gray matter-white matter interface along the corpus callosum. Glial fibrillary acidic protein (GFAP) immunohistochemistry revealed extensive reactive gliosis appearing diffusely through the bilateral cortices, hippocampi, and thalami at 48 h postinjury. Breakdown of the blood-brain barrier was demonstrated with antimouse IgG immunohistochemistry, revealing extravasation of endogenous IgG throughout the ipsilateral cortex, hippocampus, and thalamus. These results suggest that this new model of parasagittal CCI in the mouse mimics a number of well-established sequelae observed in previously characterized brain injury models using other rodent species. This mouse model may be a particularly useful experimental tool for comparing behavioral and histopathologic characteristics of traumatic brain injury in wild-type and genetically altered mice.
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                Author and article information

                Journal
                J Musculoskelet Neuronal Interact
                J Musculoskelet Neuronal Interact
                Journal of Musculoskeletal & Neuronal Interactions
                International Society of Musculoskeletal and Neuronal Interactions (Greece )
                1108-7161
                December 2015
                : 15
                : 4
                : 309-315
                Affiliations
                [1 ]Center for Musculoskeletal Surgery, Charité – University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
                [2 ]Julius Wolff Institute, Charité – University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
                [3 ]Berlin-Brandenburg Center for Regenerative Therapies, Charité – University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
                Author notes
                Corresponding author: Ricarda Locher, MD, Center for Musculoskeletal Surgery, Charité – University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany E-mail: ricarda.locher@ 123456charite.de

                The authors have no conflict of interest. This study was funded by the German Research Society (DFG, project TS 303/1-1).

                Article
                JMNI-15-309
                5628590
                26636276
                eedd2dcc-03ca-42e8-b178-d8330576de18
                Copyright: © Journal of Musculoskeletal and Neuronal Interactions

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 September 2015
                Categories
                Original Article

                traumatic brain injury,fracture healing,polytrauma,microct

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