Publications by authors named "Judith Strauß"

21 Publications

  • Page 1 of 1

Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier.

Acta Neuropathol 2020 10 11;140(4):549-567. Epub 2020 Jul 11.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood-brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
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http://dx.doi.org/10.1007/s00401-020-02187-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498485PMC
October 2020

Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS.

J Clin Invest 2020 04;130(4):1977-1990

Wihuri Research Institute and Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Angiopoietin-2 (Ang2), a ligand of the endothelial Tie2 tyrosine kinase, is involved in vascular inflammation and leakage in critically ill patients. However, the role of Ang2 in demyelinating central nervous system (CNS) autoimmune diseases is unknown. Here, we report that Ang2 is critically involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis. Ang2 expression was induced in CNS autoimmunity, and transgenic mice overexpressing Ang2 specifically in endothelial cells (ECs) developed a significantly more severe EAE. In contrast, treatment with Ang2-blocking Abs ameliorated neuroinflammation and decreased spinal cord demyelination and leukocyte infiltration into the CNS. Similarly, Ang2-binding and Tie2-activating Ab attenuated the development of CNS autoimmune disease. Ang2 blockade inhibited expression of EC adhesion molecules, improved blood-brain barrier integrity, and decreased expression of genes involved in antigen presentation and proinflammatory responses of microglia and macrophages, which was accompanied by inhibition of α5β1 integrin activation in microglia. Taken together, our data suggest that Ang2 provides a target for increasing Tie2 activation in ECs and inhibiting proinflammatory polarization of CNS myeloid cells via α5β1 integrin in neuroinflammation. Thus, Ang2 targeting may serve as a therapeutic option for the treatment of CNS autoimmune disease.
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http://dx.doi.org/10.1172/JCI130308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108925PMC
April 2020

Laquinimod, a prototypic quinoline-3-carboxamide and aryl hydrocarbon receptor agonist, utilizes a CD155-mediated natural killer/dendritic cell interaction to suppress CNS autoimmunity.

J Neuroinflammation 2019 Feb 26;16(1):49. Epub 2019 Feb 26.

Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.

Background: Quinoline-3-carboxamides, such as laquinimod, ameliorate CNS autoimmunity in patients and reduce tumor cell metastasis experimentally. Previous studies have focused on the immunomodulatory effect of laquinimod on myeloid cells. The data contained herein suggest that quinoline-3-carboxamides improve the immunomodulatory and anti-tumor effects of NK cells by upregulating the adhesion molecule DNAX accessory molecule-1 (DNAM-1).

Methods: We explored how NK cell activation by laquinimod inhibits CNS autoimmunity in experimental autoimmune encephalomyelitis (EAE), the most utilized model of MS, and improves immunosurveillance of experimental lung melanoma metastasis. Functional manipulations included in vivo NK and DC depletion experiments and in vitro assays of NK cell function. Clinical, histological, and flow cytometric read-outs were assessed.

Results: We demonstrate that laquinimod activates natural killer (NK) cells via the aryl hydrocarbon receptor and increases their DNAM-1 cell surface expression. This activation improves the cytotoxicity of NK cells against B16F10 melanoma cells and augments their immunoregulatory functions in EAE by interacting with CD155 dendritic cells (DC). Noteworthy, the immunosuppressive effect of laquinimod-activated NK cells was due to decreasing MHC class II antigen presentation by DC and not by increasing DC killing.

Conclusions: This study clarifies how DNAM-1 modifies the bidirectional crosstalk of NK cells with CD155 DC, which can be exploited to suppress CNS autoimmunity and strengthen tumor surveillance.
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http://dx.doi.org/10.1186/s12974-019-1437-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390632PMC
February 2019

Targeted delivery of glucocorticoids to macrophages in a mouse model of multiple sclerosis using inorganic-organic hybrid nanoparticles.

J Control Release 2017 01 3;245:157-169. Epub 2016 Dec 3.

Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany. Electronic address:

Glucocorticoids (GC) are widely used to treat acute relapses in multiple sclerosis (MS) patients, but their application is accompanied by side effects due to their broad spectrum of action. Here, we report on the therapeutic option to apply GC via inorganic-organic hybrid nanoparticles (IOH-NP) with the composition [ZrO][(BMP)(FMN)] (designated BMP-NP with BMP: betamethasone phosphate; FMN: flavinmononucleotide). We found that these BMP-NP have an increased cell type-specificity compared to free GC while retaining full therapeutic efficacy in a mouse model of MS. BMP-NP were preferentially taken up by phagocytic cells and modulated macrophages in vivo more efficiently than T cells. When GC were applied in the form of BMP-NP, treatment of neuroinflammatory disease in mice exclusively depended on the control of macrophage function whereas effects on T cells and brain endothelial cells were dispensable for therapeutic efficacy. Importantly, BMP-NP were not only active in mice but also showed strong activity towards monocytes isolated from healthy human volunteers. We conclude that application of GC via IOH-NP has the potential to improve MS therapy in the future.
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http://dx.doi.org/10.1016/j.jconrel.2016.12.003DOI Listing
January 2017

Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease.

Proc Natl Acad Sci U S A 2016 Mar 8;113(12):3323-8. Epub 2016 Mar 8.

Institute of Neuroimmunology and Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, D-37073 Göttingen, Germany; Max-Planck-Institute for Experimental Medicine Göttingen, D-37075 Göttingen, Germany

Multiple sclerosis (MS) is caused by T cells that are reactive for brain antigens. In experimental autoimmune encephalomyelitis, the animal model for MS, myelin-reactive T cells initiate the autoimmune process when entering the nervous tissue and become reactivated upon local encounter of their cognate CNS antigen. Thereby, the strength of the T-cellular reactivation process within the CNS tissue is crucial for the manifestation and the severity of the clinical disease. Recently, B cells were found to participate in the pathogenesis of CNS autoimmunity, with several diverse underlying mechanisms being under discussion. We here report that B cells play an important role in promoting the initiation process of CNS autoimmunity. Myelin-specific antibodies produced by autoreactive B cells after activation in the periphery diffused into the CNS together with the first invading pathogenic T cells. The antibodies accumulated in resident antigen-presenting phagocytes and significantly enhanced the activation of the incoming effector T cells. The ensuing strong blood-brain barrier disruption and immune cell recruitment resulted in rapid manifestation of clinical disease. Therefore, myelin oligodendrocyte glycoprotein (MOG)-specific autoantibodies can initiate disease bouts by cooperating with the autoreactive T cells in helping them to recognize their autoantigen and become efficiently reactivated within the immune-deprived nervous tissue.
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http://dx.doi.org/10.1073/pnas.1519608113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812745PMC
March 2016

Immunization with Immune Complexes Modulates the Fine Specificity of Antibody Responses to a Flavivirus Antigen.

J Virol 2015 Aug 27;89(15):7970-8. Epub 2015 May 27.

Department of Virology, Medical University of Vienna, Vienna, Austria

Unlabelled: The antibody response to proteins may be modulated by the presence of preexisting antigen-specific antibodies and the formation of immune complexes (ICs). Effects such as a general increase or decrease of the response as well as epitope-specific phenomena have been described. In this study, we investigated influences of IC immunization on the fine specificity of antibody responses in a structurally well-defined system, using the envelope (E) protein of tick-borne encephalitis (TBE) virus as an immunogen. TBE virus occurs in Europe and Asia and-together with the yellow fever, dengue, West Nile, and Japanese encephalitis viruses-represents one of the major human-pathogenic flaviviruses. Mice were immunized with a dimeric soluble form of E (sE) alone or in complex with monoclonal antibodies specific for each of the three domains of E, and the antibody response induced by these ICs was compared to that seen after immunization with sE alone. Immunoassays using recombinant domains and domain combinations of TBE virus sE as well as the distantly related West Nile virus sE allowed the dissection and quantification of antibody subsets present in postimmunization sera, thus generating fine-specificity patterns of the polyclonal responses. There were substantially different responses with two of the ICs, and the differences could be mechanistically related to (i) epitope shielding and (ii) antibody-mediated structural changes leading to dissociation of the sE dimer. The phenomena described may also be relevant for polyclonal responses upon secondary infections and/or booster immunizations and may affect antibody responses in an individual-specific way.

Importance: Infections with flaviviruses such as yellow fever, dengue, Japanese encephalitis, West Nile, and tick-borne encephalitis (TBE) viruses pose substantial public health problems in different parts of the world. Antibodies to viral envelope protein E induced by natural infection or vaccination were shown to confer protection from disease. Such antibodies can target different epitopes in E protein, and the fine specificities of polyclonal responses can differ between individuals. We conducted a mouse immunization study with TBE E protein alone or complexed to monoclonal antibodies specific for each of the three protein domains. We demonstrated that phenomena such as epitope shielding and antibody-induced structural changes can profoundly influence the fine specificity of antibody responses to the same immunogen. The study thus provided important new information on the potential immunomodulatory role of preexisting antibodies in a flavivirus system that can be relevant for understanding individual-specific factors influencing antibody responses in sequential flavivirus infections and/or immunizations.
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http://dx.doi.org/10.1128/JVI.00938-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505641PMC
August 2015

Variation of the specificity of the human antibody responses after tick-borne encephalitis virus infection and vaccination.

J Virol 2014 Dec 24;88(23):13845-57. Epub 2014 Sep 24.

Department of Virology, Medical University of Vienna, Vienna, Austria

Unlabelled: Tick-borne encephalitis (TBE) virus is an important human-pathogenic flavivirus endemic in large parts of Europe and Central and Eastern Asia. Neutralizing antibodies specific for the viral envelope protein E are believed to mediate long-lasting protection after natural infection and vaccination. To study the specificity and individual variation of human antibody responses, we developed immunoassays with recombinant antigens representing viral surface protein domains and domain combinations. These allowed us to dissect and quantify antibody populations of different fine specificities in sera of TBE patients and vaccinees. Postinfection and postvaccination sera both displayed strong individual variation of antibody titers as well as the relative proportions of antibodies to different domains of E, indicating that the immunodominance patterns observed were strongly influenced by individual-specific factors. The contributions of these antibody populations to virus neutralization were quantified by serum depletion analyses and revealed a significantly biased pattern. Antibodies to domain III, in contrast to what was found in mouse immunization studies with TBE and other flaviviruses, did not play any role in the human neutralizing antibody response, which was dominated by antibodies to domains I and II. Importantly, most of the neutralizing activity could be depleted from sera by a dimeric soluble form of the E protein, which is the building block of the icosahedral herringbone-like shell of flaviviruses, suggesting that antibodies to more complex quaternary epitopes involving residues from adjacent dimers play only a minor role in the total response to natural infection and vaccination in humans.

Importance: Tick-borne encephalitis (TBE) virus is a close relative of yellow fever, dengue, Japanese encephalitis, and West Nile viruses and distributed in large parts of Europe and Central and Eastern Asia. Antibodies to the viral envelope protein E prevent viral attachment and entry into cells and thus mediate virus neutralization and protection from disease. However, the fine specificity and individual variation of neutralizing antibody responses are currently not known. We have therefore developed new in vitro assays for dissecting the antibody populations present in blood serum and determining their contribution to virus neutralization. In our analysis of human postinfection and postvaccination sera, we found an extensive variation of the antibody populations present in sera, indicating substantial influences of individual-specific factors that control the specificity of the antibody response. Our study provides new insights into the immune response to an important human pathogen that is of relevance for the design of novel vaccines.
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http://dx.doi.org/10.1128/JVI.02086-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248988PMC
December 2014

Physeal bystander effects in rhabdomyosarcoma radiotherapy: experiments in a new xenograft model.

Sarcoma 2011 17;2011:815190. Epub 2011 Apr 17.

Department of Orthopaedic Surgery, Musculoskeletal Sciences Research Center, Institute for Human Performance, SUNY Upstate Medical University, 505 Irving Avenue, Syracuse, NY 13210, USA.

Radiotherapy used in the treatment of pediatric musculoskeletal sarcomas may result in crippling defects of skeletal growth. Several radioprotective strategies have shown potential for preserving function of the irradiated epiphysis but have not been evaluated in a tumor-bearing animal model. We developed two bioluminescent human rhabdomyosarcoma cell lines that were used to establish xenograft tumors in skeletally immature mice. Bioluminescence imaging and radiography allowed serial evaluation of tumor growth and tibial elongation following localized radiotherapy. High-dose (10 Gy) radiotherapy significantly reduced tumor growth velocity and prolonged the median survival of tumor-bearing mice but also resulted in a significant 3.3% shortening of the irradiated limb. Exposure to a lower, 2 Gy dose resulted in 4.1% decrease in limb length but did not extend survival. This new model provides a clinically relevant means to test the efficacy and safety of novel radioprotectant and radiorecovery strategies for use in this context.
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http://dx.doi.org/10.1155/2011/815190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087963PMC
July 2011

Microarray cluster analysis of irradiated growth plate zones following laser microdissection.

Int J Radiat Oncol Biol Phys 2009 Jul;74(3):949-56

SUNY Upstate Medical University, Syracuse, NY, USA.

Purpose: Genes and pathways involved in early growth plate chondrocyte recovery after fractionated irradiation were sought as potential targets for selective radiorecovery modulation.

Materials And Methods: Three groups of six 5-week male Sprague-Dawley rats underwent fractionated irradiation to the right tibiae over 5 days, totaling 17.5 Gy, and then were killed at 7, 11, and 16 days after the first radiotherapy fraction. The growth plates were collected from the proximal tibiae bilaterally and subsequently underwent laser microdissection to separate reserve, perichondral, proliferative, and hypertrophic zones. Differential gene expression was analyzed between irradiated right and nonirradiated left tibia using RAE230 2.0 GeneChip microarray, compared between zones and time points and subjected to functional pathway cluster analysis with real-time polymerase chain reaction to confirm selected results.

Results: Each zone had a number of pathways showing enrichment after the pattern of hypothesized importance to growth plate recovery, yet few met the strictest criteria. The proliferative and hypertrophic zones showed both the greatest number of genes with a 10-fold right/left change at 7 days after initiation of irradiation and enrichment of the most functional pathways involved in bone, cartilage, matrix, or skeletal development. Six genes confirmed by real-time polymerase chain reaction to have early upregulation included insulin-like growth factor 2, procollagen type I alpha 2, matrix metallopeptidase 9, parathyroid hormone receptor 1, fibromodulin, and aggrecan 1.

Conclusions: Nine overlapping pathways in the proliferative and hypertrophic zones (skeletal development, ossification, bone remodeling, cartilage development, extracellular matrix structural constituent, proteinaceous extracellular matrix, collagen, extracellular matrix, and extracellular matrix part) may play key roles in early growth plate radiorecovery.
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http://dx.doi.org/10.1016/j.ijrobp.2008.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743722PMC
July 2009

Neuroprotective effects of erythropoietin on acute metabolic and pathological changes in experimentally induced neurotrauma.

J Neurosurg 2008 Oct;109(4):708-14

Department of Neurosurgery, Upstate Medical University, State University of New York, Syracuse, New York 13210, USA.

Object: Head trauma is a dynamic process characterized by a cascade of metabolic and molecular events. Erythropoietin (EPO) has been shown to have neuroprotective effects in animal models of traumatic brain injury (TBI). Acute in vivo mechanisms and pathological changes associated with EPO following TBI are unknown. In this study the authors compare acute metabolic and pathological changes following TBI with and without systemically administered EPO.

Methods: Right frontal lobe microdialysis cannulae and right parietal lobe percussion hubs were inserted into 16 Sprague-Dawley rats. After a 4- to 5-day recovery, TBI was induced via a DragonFly fluid-percussion device at 2.5-2.8 atm. Rats were randomized into 2 groups, which received 5000 U/kg EPO or normal saline intraperitoneally 30 minutes after TBI. Microdialysis samples for glucose, lactate, pyruvate, and glutamate were obtained every 25 minutes for 10 hours. Rats were killed, their brains processed for light microscopy, and sections stained with H & E.

Results: Erythropoietin administered 30 minutes after TBI directly affects acute brain metabolism. Brains treated with EPO maintain higher levels of glucose 4-10 hours after TBI (p<0.01), lower levels of lactate 6-10 hours after TBI (p<0.01), and lower levels of pyruvate 7.5-10 hours after TBI (p<0.01) compared with saline-treated controls. Erythropoietin maintains aerobic metabolism after TBI. Systemic EPO administration reduces acute TBI-induced lesion volume (p<0.05).

Conclusions: Following TBI, neuron use initially increases, with subsequent depletion of extracellular glucose, resulting in increased levels of extracellular lactate and pyruvate. This energy requirement can result in cell death due to increased metabolic demands. These data suggest that the neuroprotective effect of EPO may be partially due to improved energy metabolism in the acute phase in this rat model of TBI.
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http://dx.doi.org/10.3171/JNS/2008/109/10/0708DOI Listing
October 2008

Histomorphometric evidence of growth plate recovery potential after fractionated radiotherapy: an in vivo model.

Radiat Res 2008 Sep;170(3):284-91

Musculoskeletal Science Research Center, Department of Orthopedic Surgery, Upstate Medical University, Syracuse, New York, USA.

This study evaluated the hypothesis that early growth plate radiorecovery is evident by growth rate, histomorphometric and immunohistochemical end points after exposure to clinically relevant fractionated radiation in vivo. Twenty-four weanling 5-week-old male Sprague-Dawley rats were randomized into eight groups. In each animal, the right distal femur and proximal tibia were exposed to five daily fractions of 3.5 Gy (17.5 Gy) with the left leg serving as a control. Rats were killed humanely at 7, 8, 9, 10, 11, 14, 15 and 16 days after the first day of radiation exposure. Quantitative end points calculated included individual zonal and overall growth plate heights, area matrix fraction, OTC-labeled growth rate, chondrocyte clone volume and numeric density, and BrdU immunohistochemical labeling for proliferative index. Transient postirradiation reductions occurred early and improved during observation for growth rate, proliferative indices, transitional/hypertrophic zone matrix area fraction, proliferative height, and clonal volume. Reserve and hypertrophic zone height remained increased during the period of observation. The current model, using a more clinically relevant fractionation scheme than used previously, shows early evidence of growth plate recovery and provides a model that can be used to correlate temporal changes in RNA and protein expression during the early period of growth plate recovery.
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http://dx.doi.org/10.1667/RR1254.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556978PMC
September 2008

Ontogeny of skeletal maturation in the juvenile rat.

Anat Rec (Hoboken) 2008 Mar;291(3):283-92

SUNY Upstate Medical University, Department of Orthopedic Surgery, 3120 Institute for Human Performance, Musculoskeletal Sciences Research Center, Syracuse, NY 13210, USA.

Systemic regulation of the cellular processes that produce endochondral elongation and endochondral mineralization during postnatal skeletal maturation are not completely understood. In particular, a mechanism coupling the decline of cellular activity in the bone microenvironment to the onset of sexual maturity remains elusive. The purpose of this study was to empirically integrate the dynamic progression of bone mineral accrual and endochondral elongation as a function of animal age in growing male and female Sprague-Dawley rats. We used serial dual-energy X-ray absorptiometry (DXA) and radiography to study the temporal progression of bone growth and mineral accrual from weaning to adulthood. We observed that skeletal maturation proceeds in a pattern adequately described by the Gompertz function. During this period of growth, we found that serum markers of osteoblastic bone formation declined with age, while osteoclastic bone resorption activity remained unchanged. We also report a slight lag in the age at inflection in the rate of bone mineral accrual relative to the rate of tibial elongation and that both endochondral processes eventually come to asymptotic equilibrium by approximately 20 weeks of age. In addition, we studied tibial growth plate histomorphometry at select time points through 1 year of age. We report that, despite the histologic persistence of physeal cartilage, very little proliferative or elongative activity was measured in this tissue beyond 20 weeks of age. Taken together, these data provide insight to the temporal coordination of postnatal endochondral growth processes.
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http://dx.doi.org/10.1002/ar.20650DOI Listing
March 2008

Restoration of growth plate function following radiotherapy is driven by increased proliferative and synthetic activity of expansions of chondrocytic clones.

J Orthop Res 2006 Oct;24(10):1945-56

Musculoskeletal Sciences Research Center, Department of Orthopaedic Surgery, 3120 Institute for Human Performance, SUNY Upstate Medical University, 505 Irving Avenue, Syracuse, New York 13210, USA.

Radiation therapy encompassing an active epiphysis can negatively impact the potential for bone growth by disrupting cell-cycle progression and accelerating apoptosis and terminal differentiation in physeal chondrocytes. Despite functional derangement following radiation exposure, the irradiated growth plate retains a capacity for regeneration and recovery of growth. The purpose of this study was to characterize the initial sequence of events leading to functional growth recovery in irradiated weanling rat growth plates. We hypothesized that growth in an irradiated epiphysis would be partially restored due to the expansion of chondrocytic clones. Stereological histomorphometry was used to compare chondrocytic cell and matrix turnover between the first and second week following irradiation, and to determine the relative contribution of each of the cellular and extracellular matrix (ECM) compartments to growth. We found that restoration of growth in the irradiated limb was strongly associated with the proliferative activity and production of ECM by these chondrocytic clones, as they expand in average volume, but not in numerical density. We conclude that chondrocytes forming expansive clones and exhibiting increased mitotic and matrix synthesis activity initiate the early restoration of function in the irradiated growth plate, and would be a logical target for strategies to restore full growth potential.
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http://dx.doi.org/10.1002/jor.20251DOI Listing
October 2006

Soft tissue osteochondroma: case report and immunohistochemistry for parathyroid hormone-related protein.

Ann Diagn Pathol 2006 Aug;10(4):222-9

Department of Orthopedic Surgery, Upstate Medical University, State University of New York at Syracuse, Syracuse, NY 13210, USA.

Surface lesions of bone usually present little diagnostic dilemma because the majority are conventional osteochondromas. Other surface bone lesions include periosteal chondroma, periosteal chondrosarcoma, and parosteal osteosarcoma. Mineralized soft tissue lesions such as myositis ossificans, synovial chondroma, and synovial sarcoma may present in a similar fashion when they occur in a juxtaarticular position. The soft tissue osteochondroma or paraarticular osteochondroma may simulate some of these more aggressive tumors, and its recognition is important to avoid overtreatment. A case of an 11-year-old male with a soft tissue osteochondroma is reported to illustrate the characteristic radiographic and histological features of this rare entity. No prior reports have examined soft tissue osteochondroma for expression of parathyroid hormone related protein, an established cartilage tumor proliferative mitogen.
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http://dx.doi.org/10.1016/j.anndiagpath.2005.12.006DOI Listing
August 2006

Combination radioprotectors maintain proliferation better than single agents by decreasing early parathyroid hormone-related protein changes after growth plate irradiation.

Radiat Res 2006 Mar;165(3):350-8

Department of Orthopedic Surgery, SUNY Upstate Medical University, Syracuse, New York 13210, USA.

Our hypothesis was that combinations of radioprotectors would be more effective than individual agents in minimizing the effects of radiation on the growth plate after single-fraction hind-limb irradiation of Sprague-Dawley rats. At 2 days postirradiation, the decrease in parathyroid hormone-related protein and parathyroid hormone receptor 1 expression in the irradiated growth plate transitional and hypertrophic zones was reversed in both of the combination groups but persisted in the groups treated with the individual drugs. By 2 weeks, positive findings unique to the combination-treatment animals included greater mean proliferation in the irradiated growth plate than on the contralateral side, smaller limb length discrepancies, reversal of the increased overall matrix area fraction, and reversal of the usual deficiency in Indian hedgehog staining in the irradiated hypertrophic zone. While all treatments had a positive effect in reversing the decrease in B-cell leukemia 2 protein and coincident increase in Bax previously observed 2 weeks postirradiation, the two combination groups had a more robust effect. Combinations of radioprotectors may achieve their beneficial additive effects in the growth plate by decreasing the usual early drop in parathyroid hormone-related protein and parathyroid hormone receptor 1 after irradiation, resulting in a cascade of parathyroid hormone-related protein-mediated events.
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http://dx.doi.org/10.1667/rr3504.1DOI Listing
March 2006

Radioprotectant combinations spare radiation-induced damage to the physis more than fractionation alone.

Int J Radiat Biol 2005 Oct;81(10):759-65

Musculoskeletal Research Laboratory of Department of Orthopedic Surgery, Institute for Human Performance at SUNY Upstate Medical University, Syracuse, New York 13210, USA.

Purpose: The aim of this study was to determine if fractionation and individual or combinations of radioprotectants could minimize damage to physeal longitudinal growth in an animal model to any greater extent than fractionation alone.

Materials And Methods: Sixty-three weanling male Sprague-Dawley rats were randomized into seven equal groups. Five groups received a total 25 Gy radiation exposure in three equal fractions to the right knee with the left as non-irradiated control. For each group, pentoxifylline, misoprostol, and amifostine were given individually and amifostine was also given in combination with each of the other drugs prior to the radiation fractions. One group each received 25 Gy in one or three fractions without radioprotection. At six weeks, limb lengths and histomorphometry were assessed.

Results: The single fraction of 25 Gy caused a mean tibial length discrepancy of 24.4%. Fractionation decreased this to 18.8% (p < 0.001). Beyond fractionation alone, the mean femoral length discrepancies were significantly decreased by each of the added individual and combination radioprotectant drugs (p < 0.0004). The smallest absolute femoral length discrepancy (11%) was achieved with fractionation and the combination of amifostine and misoprostol.

Conclusions: Radioprotectants may be beneficial in growth plate radioprotection, alone or in combination.
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http://dx.doi.org/10.1080/09553000500495710DOI Listing
October 2005

Combinations of radioprotectants spare radiation-induced damage to the physis.

Clin Orthop Relat Res 2004 Sep(426):110-6

Department of Orthopedic Surgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

Radiotherapy used in the treatment of bone and soft tissue sarcomas in pediatric patients often results in undesirable growth plate damage. Radioprotectants may hold promise in the selective protection of growth plate tissue in this setting. In an animal model, the hypothesis tested was that pentoxifylline, selenium, or misoprostol, used in combination with amifostine, would significantly reduce longitudinal growth loss during one radiation dose exposure to a greater extent than the protection provided by only amifostine without increased morbidity or mortality or adverse effects on bone mineral density. Amifostine alone and in combination with each of the other radioprotectants resulted in limb discrepancy reduction to levels significantly less than radiated controls. The tibial length discrepancy in the selenium and amifostine group was 12.1 +/- 0.8%, less than the 15.5 +/- 2.6% tibial length discrepancy in the animals treated with amifostine alone, and less than the mean 18.8% tibial length discrepancy in the radiated limbs without radioprotection. There were no adverse effects on bone density in any group, but the selenium and amifostine group showed some increased mortality. Combinations of amifostine with these radioprotectants show efficacy in growth plate radioprotection and therefore warrant additional study in a clinically relevant fractionated model.
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http://dx.doi.org/10.1097/01.blo.0000131247.18112.0fDOI Listing
September 2004

Decreased proliferation precedes growth factor changes after physeal irradiation.

Clin Orthop Relat Res 2004 May(422):233-42

Departments of Orthopedics and Pathology, SUNY Upstate Medical University, Syracuse, NY, USA.

The effects of irradiation on growth plate chondrocytes and mediators of chondrocytic differentiation are poorly understood. In earlier work on rat growth plate changes 1/2 to 4 weeks after irradiation, a nadir was identified at 1 week in proliferation and growth factor expression coincident with maximal histomorphometric derangement. The purpose of this study was to determine the earlier sequential relationship of proliferative, growth factor, and histomorphometric changes after irradiation leading to the 1-week nadir. Twenty-four weanling 5-week-old male Sprague-Dawley rats had right knee irradiation with single fraction 17.5 Gy whereas the left leg served as an internal control. The earliest change identified was a significant decrease in BrdU evidence of proliferative activity between 6 and 12 hours after irradiation, which persisted through 48 hours. Twelve to 24 hours after irradiation, caspase-3 staining for apoptosis was higher than that in growth plates not having received radiotherapy. Histomorphometric changes after irradiation were observed as early as 24 hours. Growth factors and their downstream antiapoptotic and proapoptotic mediators did not differ significantly between limbs through 48 hours. The current study suggests that decreased proliferation and apoptosis precede any change in histomorphometric features of the growth plate after irradiation and that decreased growth factor expression occurs later.
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http://dx.doi.org/10.1097/01.blo.0000129344.28160.9dDOI Listing
May 2004

Temporal changes in PTHrP, Bcl-2, Bax, caspase, TGF-beta, and FGF-2 expression following growth plate irradiation with or without radioprotectant.

J Histochem Cytochem 2004 Feb;52(2):157-67

Departments of Orthopedics and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.

This study examined temporal changes in growth plate apoptosis molecules and growth factors in an animal model of radiation injury with and without a radioprotectant. Thirty weanling 5-week Sprague-Dawley rats underwent right knee irradiation with single-fraction 17.5 Gy while the left served as internal control. Six animals each were sacrificed at 0.5, 1, 2, 3, or 4 weeks after irradiation. Half of the animals received pretreatment with amifostine (WR-2721) radioprotectant. Immunohistochemical staining for PTHrP, Bcl-2, Bax, caspase-3, FGF-2, and TGF-beta was performed. PTHrP decreased to a nadir at 1 week after irradiation but rebounded to above control levels at 2 weeks in the reserve and transitional zones. The radioprotectant amifostine blunted the decrease in PTHrP but kept PTHrP expression lower than controls during the rebound phase in untreated irradiated animals. Hypertrophic zone Bax expression was decreased by amifostine in both irradiated and non-irradiated limbs at 1 and 2 weeks. FGF, TGF-beta, Bcl-2, and caspase levels generally decreased at 1 week and returned thereafter toward control levels. These findings underscore the importance of PTHrP in response to growth plate irradiation and show the novel finding of a decrease in Bax expression with amifostine pretreatment.
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http://dx.doi.org/10.1177/002215540405200203DOI Listing
February 2004

Transiently increased bone density after irradiation and the radioprotectant drug amifostine in a rat model.

Am J Clin Oncol 2003 Aug;26(4):e106-14

Musculoskeletal Research Center, Institute for Human Performance, Department of Orthopaedic Surgery, SUNY Upstate Medical University at Syracuse, Syracuse, New York 13202, USA.

At therapeutic levels in pediatric patients, radiation causes damage to the growth plate and contributes to growth deformity and fractures. The purpose of this project was to examine the effects of x-ray irradiation on regional bone mineral density (BMD) and osteoclast histology of rat bone with and without radioprotectant amifostine (AMF) pretreatment. Seventy-two weanling rats had their right knee irradiated with single fraction 17.5 Gy, whereas the left leg was used as an internal control. Twelve animals were euthanized at each of 6 time periods (0.5-6 wk) after irradiation, half having received 100 mg/kg amifostine. BMD (g/cm3) was determined for both the right and left femurs using peripheral quantitative computed tomography (CT) (pQCT). Tibial sections were stained for osteoclasts/chondroclasts with tartrate-resistant acid phosphatase. Statistically significant increases in BMD within the radiation field were seen in the treatment groups' right irradiated legs over the control unirradiated left legs at all time points from 0.5 through 6 weeks. Anatomically, a peak in BMD occurs in the region immediately adjacent to the chondro-osseous junction at 2 weeks after irradiation and then moves proximally within the adjacent metaphysis after 3 weeks. Corresponding to these findings, histologically a 2-week nadir occurs after irradiation in osteoclasts/chondroclast numbers adjacent to the chondro-osseous junction with a 71.9% decrease compared with controls (p <0.05). At 3 weeks, the numbers of osteoclasts/chondroclasts in this region have increased to 47.4% greater than the control legs (p <0.03) The animals receiving amifostine had BMD that was consistently closer to controls only adjacent to the chondro-osseous junction at 0.5, 2, and 3 weeks and osteoclast/chondroclast numbers that were closer to controls only at 4 weeks.
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http://dx.doi.org/10.1097/01.COC.0000077934.48841.40DOI Listing
August 2003

Sequential histomorphometric analysis of the growth plate following irradiation with and without radioprotection.

J Bone Joint Surg Am 2003 Jul;85(7):1302-13

Musculoskeletal Research Laboratory, Department of Orthopedic Surgery, Institute for Human Performance at State University of New York Upstate Medical University, Syracuse 13210, USA.

Background: The availability of radioprotectant drugs that selectively protect normal cells but not tumor cells has rekindled interest in the effects of irradiation on the growth plate. The purpose of the present study was to quantitatively examine the sequential histomorphometric effects of irradiation and pretreatment with a free radical scavenger radioprotectant, amifostine, on the growth plate over time.

Methods: Sixty four-week-old male Sprague-Dawley rats were randomized into five groups of twelve animals that were to be killed at 0.5, one, two, three, or four weeks after irradiation. One-half of the animals also received amifostine (100 mg/kg) prior to irradiation. In all animals, the right knee was treated with a single 17.5-Gy dose of radiation. End points were assessed with quantitative histomorphometric analysis of the growth plate, BrdU labeling for evidence of proliferation, evaluation of chondroclast cellularity, and determination of growth rates by means of oxytetracycline labeling.

Results: The mean lengths of the femur, tibia, and hind limb continued to increase at each time-interval following treatment, but by one week the mean limb length was 4% less on the irradiated side than on the control side, and this difference remained significant for four weeks (p < 0.05). The proximal tibial growth rate decreased during the first week to 18% of the control level. Nevertheless, growth continued even at the earliest time-periods, began to return toward normal at two weeks, and ultimately returned to at least 80% of normal by four weeks after irradiation. The area fraction of matrix in the hypertrophic zone increased initially and returned to control levels at three and four weeks. The administration of the radioprotectant resulted in significant increases in growth, growth rate, growth plate height, hypertrophic zonal height, and chondroclast profiles compared with the values for limbs in which irradiation had not been preceded by treatment with amifostine.

Conclusions: We found an initially profound but transient direct inhibitory effect of irradiation on growth plate chondrocytes. Recovery of growth plate function after irradiation corresponded temporally with the appearance of newly formed islands of proliferating chondrocytes. Accumulation of matrix led to a transient increase in overall growth plate height, which was most pronounced in the hypertrophic zone. This was due, in part, to the sensitivity of chondroclasts to irradiation. The radioprotectant amifostine reduced these effects on growth rate, growth plate height, matrix accumulation, and limb length.
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http://dx.doi.org/10.2106/00004623-200307000-00017DOI Listing
July 2003