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The cytosolic protein Sharpin is a component of the linear ubiquitin chain assembly complex, which regulates NF-κB signaling in response to specific ligands, such as TNF-α. Its inactivating mutation in chronic proliferative dermatitis mutation (Cpdm) mice causes multiorgan inflammation, yet this phenotype is not transferable into wild-type mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, and that this osteopenia is corrected by Tnf deletion. Because the cellular mechanism underlying this pathology, however, was still undefined, we performed a thorough skeletal phenotyping of Cpdm mice on the basis of nondecalcified histology and cellular and dynamic histomorphometry. We show that the trabecular and cortical osteopenia in Cpdm mice is solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. Consistently, Cpdm primary calvarial cells display reduced osteogenic capacity ex vivo, and the same was observed with CD11b(-) bone marrow cells. Unexpectedly, short-term treatment of these cultures with TNF-α did not reveal an impaired molecular response in the absence of Sharpin. Instead, genome-wide and gene-specific expression analyses revealed that Cpdm mesenchymal cells display increased responsiveness toward TNF-α-induced expression of specific cytokines, such as CXCL5, IL-1ß, and IL-6. Therefore, our data not only demonstrate that the skeletal defects of Cpdm mice are specifically caused by impaired differentiation of osteoprogenitor cells, they also suggest that increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype of Cpdm mice.
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Células da Medula Óssea/imunologia , Proteínas de Transporte/imunologia , Diferenciação Celular/imunologia , Células-Tronco Mesenquimais/imunologia , Osteogênese/imunologia , Animais , Células da Medula Óssea/patologia , Proteínas de Transporte/genética , Diferenciação Celular/genética , Citocinas/genética , Citocinas/imunologia , Dermatite/genética , Dermatite/imunologia , Dermatite/patologia , Peptídeos e Proteínas de Sinalização Intracelular , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Mutantes , Osteogênese/genéticaRESUMO
INTRODUCTION: Acute compartment syndrome (ACS) is an orthopaedic emergency affecting all age groups, yet diagnosis proves particularly difficult within the paediatric population and especially in the absence of fractures. CASE PRESENTATION: In this case report, we detail a rare instance of a non-fracture acute compartment syndrome (NFACS) in a 14-year-old boy, initially missed due to lack of suspicion. Symptoms included swelling, severe pain, and initial paresthesia in the hand. Despite prompt forearm fasciotomy, severe post-traumatic Volkmann contracture ensued, resulting in limited upper extremity function despite multiple corrective surgeries. CLINICAL DISCUSSION: Acute compart syndromes, occurring without fractures, often faces delayed diagnosis, particularly in paediatrics population. Clinical examination remains the diagnostic gold standard, with analgesia refractory pain warranting suspicion. Additional diagnostic criteria like ultrasound, MRI or CK blood values can be evaluated with reservation, especially in the paediatric population. CONCLUSION: This case highlights the importance of increased vigilance in diagnostics for NFACS especially in children, in order to not overlook NFACS, due to the wide variability in the aetiology and clinical appearance. We emphasize the relevance of clinical diagnostics and point out an increased awareness of NFACS in analgesic refractory pain.
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Monteggia injuries are rare childhood injuries. In 25-50% of cases, however, they continue to be overlooked, leading to a chronic Monteggia injury. Initially, the chronic Monteggia injury is only characterized by a moderate motion deficit, which is often masked by compensatory movements. Later, however, there is a progressive valgus deformity, neuropathy of the ulnar nerve and a progressive deformity of the radial head ("mushroom deformity") with ultimately painful radiocapitellar arthrosis. In the early stages, when the radial head is not yet deformed and there is no osteoarthritis in the humeroradial joint, these injuries can be treated with reconstruction procedures. This can be achieved either by an osteotomy of the proximal ulna with or without gradual lengthening. If there is already a severe deformity of the radial head and painful osteoarthritis, only rescue procedures such as functional radial head resection or radial head resection with or without hemi-interposition arthroplasty can be used to improve mobility and, above all, to eliminate pain. In this review article, we provide an overview of the current treatment options of chronic Monteggia injury in children and adolescents and present a structured treatment algorithm depending on the chronicity and dysplastic changes.
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BACKGROUND: Osteochondral fractures (OCF) are traumatic shearing injuries to portions of cartilage and bone. The most common cause is patellar dislocation, with the main localisation being the medial patellar facet and the lateral femoral condyle. They can occur in all age groups. DIAGNOSIS: Clinically, there is a painful knee joint effusion (haemarthrosis) with a "dancing patella". This is usually accompanied by restricted movement and/or a locking phenomenon. In addition to the standard Xray of the knee in three planes (lateral, anterior-posterior and tangential patella), an MRI should be performed promptly in the case of haemarthrosis and suspicious symptoms, as concomitant injuries are present in up to 70% of cases. TREATMENT: The aim of treatment is to restore joint congruence in order to prevent the risk of secondary osteoarthritis. Small chondral and stable osteochondral fractures can be treated conservatively. Surgery is indicated for all other OCFs. In addition to refixation with various materials (bioresorbable screws, bone plugs, suture material and Kirschner wires), cartilage regeneration procedures (AMIC, MACI, OAT, etc.) are available for late diagnosed or non-refixable fragments. However, the number of cases is small. CONCLUSION: Osteochondral fractures are rare injuries in children and adolescents. Prompt MRI is recommended for diagnosis in cases of suspected OCF. Refixation is the preferred treatment method, with bioresorbable implants showing promising results in reducing the need for additional surgery. The risk of secondary osteoarthritis can be reduced with regular treatment.
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BACKGROUND: Whole-Body CT (WBCT) is frequently used in emergency situations for promptly diagnosing paediatric polytrauma patients, given the challenges associated with obtaining precise details about the mechanism and progression of trauma. However, WBCT does not lead to reduced mortality in paediatric patients, but is associated with high radiation exposure. We therefore wanted to develop a screening tool for CT demand-driven emergency room (ER)-trauma diagnostic to reduce radiation exposure in paediatric patients. METHODS: A retrospective study in a Level I trauma centre in Germany was performed. Data from 344 paediatric emergency patients with critical mechanism of injury who were pre-announced by the ambulance for the trauma room were collected. Patients' symptoms, clinical examination, extended Focused Assessment with Sonography for Trauma (eFAST), routinely, laboratory tests and blood gas and - when obtained - WBCT images were analysed. To identify potential predictors of severe injuries (ISS > 23), 300 of the 344 cases with complete data were subjected to regression analyses model. RESULTS: Multiple regression analysis identified cGCS, base excess (BE), medically abnormal results from eFAST screening, initial unconsciousness, and injuries involving three or more body regions as significant predictors for a screening tool for decision-making to perform WBCT or selective CT. The developed Paediatric polytrauma CT-Indication (PePCI)-Score was divided into three risk categories and achieved a sensitivity of 87 % and a specificity of 71 % when comparing the low and medium risk groups with the high risk group. Comparing only the low-risk group with the high-risk group for the decision to perform WBCT, 32/35 (91 %) of patients with an ISS >23 were correctly identified, as were 124/137 (91 %) with lower ISS scores. CONCLUSION: With the newly developed PePCI-Score, the frequency of WBCT in a paediatric emergency patients collective can be significantly reduced according to our data. After prospective validation, the initial assessment of paediatric trauma patients in the future could be made not only by the mechanism of injury, but also by the new PePCI-Score, deriving on clinical findings after thorough clinical assessment and the discretion of the trauma team.
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Traumatismo Múltiplo , Imagem Corporal Total , Humanos , Criança , Estudos Retrospectivos , Prognóstico , Imagem Corporal Total/métodos , Tomografia Computadorizada por Raios X/métodos , Escala de Gravidade do FerimentoRESUMO
PURPOSE: In pediatric population, large soft tissue defects occur in avulsion injuries. In addition to the challenges of primary surgical therapy, elasticity, appearance and function of the scar in children are of crucial importance, especially in the context of body growth. So far various flaps, plasties, skin grafts and dermal substitutes have become established, although infections and skin shrinkage remain challenging. In 2020, a new skin substitute material-NovoSorb® Biodegradable Temporizing Matrix (BTM)-was introduced in Europe for temporary wound closure and tissue regeneration. The aim of this study was to evaluate the value of BTM in pediatric patients. METHODS: The study included all children treated with BTM after traumatic soft tissue defects following limb avulsion injuries between June 2021 and June 2023 at a university hospital. RESULTS: 7 patients with limb avulsion injuries were treated with BTM, 4 boys, 3 girls. Mean age was 6.5 years (2-11 years) at the time of BTM placement. 4/7 had concomitant fractures. BTM was used successfully in all cases, infection did not occur, skin shrinkage was seen in one case. Split thickness skin graft (STSG) after BTM application was performed in average after 33 days (26 to 39 days). Limitations of this study were highlighted. CONCLUSION: BTM is a promising alternative for reconstruction of complex trauma extremity wounds in children following avulsion injuries, even in cases of concomitant bone injuries. Interpretation may be limited by sample size.
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Interleukin-33 (IL-33) is the most recently identified member of the IL-1 family of cytokines, which is primarily known for its proinflammatory functions. We have previously reported that IL-33 is expressed by bone-forming osteoblasts, and that administration of recombinant IL-33 to bone marrow cultures inhibits their differentiation into bone-resorbing osteoclasts. Likewise, while the inhibitory effect of IL-33 on osteoclast differentiation was fully abolished in cultures lacking the IL-33 receptor ST2, mice lacking ST2 displayed low bone mass caused by increased osteoclastogenesis. Although these data suggested a physiological role of IL-33 as an inhibitor of bone resorption, direct in vivo evidence supporting such a function was still missing. Here we describe the generation and bone histomorphometric analysis of a transgenic mouse model (Col1a1-Il33) over-expressing IL-33 specifically in osteoblasts. While we did not observe differences in osteoblast number and bone formation between wildtype and Col1a1-Il33 mice, the number of osteoclasts was significantly reduced compared to wildtype littermates in two independent transgenic lines. Since we did not observe quantitative differences in the populations of eosinophils, neutrophils, basophils or M2-macrophages from the bone marrow of wildtype and Col1a1-Il33 mice, our data demonstrate that an inhibition of osteoclastogenesis is one of the major physiological functions of IL-33, at least in mice.
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Interleucinas/fisiologia , Osteoblastos/fisiologia , Animais , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Interleucina-33 , Interleucinas/genética , Camundongos , Camundongos Transgênicos , Osteoblastos/citologia , TransgenesAssuntos
Moldes Cirúrgicos , Fraturas do Rádio , Traumatismos do Punho , Humanos , Fraturas do Rádio/cirurgia , Fraturas do Rádio/diagnóstico por imagem , Traumatismos do Punho/cirurgia , Traumatismos do Punho/diagnóstico por imagem , Consolidação da Fratura/fisiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/etiologia , Fraturas Salter-Harris/cirurgia , Fratura-Luxação/cirurgia , Fratura-Luxação/diagnóstico por imagem , Fraturas do PunhoRESUMO
Chemokines play crucial roles in the recruitment of specific hematopoietic cell types, and some of them have been suggested to be involved in the regulation of bone remodeling. Because we have previously observed that chemokine (C-C motif) ligand 2 (Ccl2) and Ccl5 are direct target genes of noncanonical Wnt signaling in osteoblasts, we analyzed the skeletal phenotypes of Ccl2-deficient and Ccl5-deficient mice. In line with previous studies, Ccl2-deficient mice display a moderate reduction of osteoclastogenesis at the age of 6 months. In contrast, 6-month-old Ccl5-deficient mice display osteopenia associated with decreased bone formation and increased osteoclastogenesis. Moreover, unlike in wild-type and Ccl2-deficient mice, large areas of their trabecular and endocortical bone surfaces are not covered by osteoblasts or bone-lining cells, and this is associated with a severe reduction of endosteal bone formation. Although this phenotype diminishes with age, it is important that we could further identify a reduced number of osteal macrophages in 6-month-old Ccl5-deficient mice, because this cell type has previously been reported to promote endosteal bone formation. Because Ccl5-deficient mice also display increased osteoclastogenesis, we finally addressed the question of whether osteal macrophages could differentiate into osteoclasts and/or secrete inhibitors of osteoclastogenesis. For that purpose we isolated these cells by CD11b affinity purification from calvarial cultures and characterized them ex vivo. Here we found that they are unable to differentiate into osteoblasts or osteoclasts, but that their conditioned medium mediates an antiosteoclastogenic effect, possibly caused by interleukin-18 (IL-18), an inhibitor of osteoclastogenesis expressed by osteal macrophages. Taken together, our data provide in vivo evidence supporting the previously suggested role of Ccl5 in bone remodeling. Moreover, to the best of our knowledge, Ccl5-deficient mice represent the first model with a spontaneous partial deficiency of osteal macrophages, a recently identified cell type, whose impact on bone remodeling is just beginning to be understood.
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Quimiocina CCL5/deficiência , Osteoclastos/metabolismo , Osteogênese , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Remodelação Óssea , Diferenciação Celular , Separação Celular , Células Cultivadas , Quimiocina CCL2/deficiência , Quimiocina CCL2/metabolismo , Quimiocina CCL5/metabolismo , Meios de Cultivo Condicionados/farmacologia , Hematopoese , Interleucina-18/farmacologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia , Células-Tronco/metabolismo , Tíbia/metabolismo , Tíbia/patologiaRESUMO
Since the hematopoetic system is located within the bone marrow, it is not surprising that recent evidence has demonstrated the existence of molecular interactions between bone and immune cells. While interleukin 1 (IL-1) and IL-18, two cytokines of the IL-1 family, have been shown to regulate differentiation and activity of bone cells, the role of IL-33, another IL-1 family member, has not been addressed yet. Since we observed that the expression of IL-33 increases during osteoblast differentiation, we analyzed its possible influence on bone formation and observed that IL-33 did not affect matrix mineralization but enhanced the expression of Tnfsf11, the gene encoding RANKL. This finding led us to analyze the skeletal phenotype of Il1rl1-deficient mice, which lack the IL-33 receptor ST2. Unexpectedly, these mice displayed normal bone formation but increased bone resorption, thereby resulting in low trabecular bone mass. Since this finding suggested a negative influence of IL-33 on osteoclastogenesis, we next analyzed osteoclast differentiation from bone marrow precursor cells and observed that IL-33 completely abolished the generation of TRACP(+) multinucleated osteoclasts, even in the presence of RANKL and macrophage colony-stimulating factor (M-CSF). Although our molecular studies revealed that IL-33 treatment of bone marrow cells caused a shift toward other hematopoetic lineages, we further observed a direct negative influence of IL-33 on the osteoclastogenic differentiation of RAW264.7 macrophages, where IL-33 repressed the expression of Nfatc1, which encodes one of the key transciption factors of osteoclast differentiation. Taken together, these findings have uncovered a previously unknown function of IL-33 as an inhibitor of bone resorption.
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Células da Medula Óssea/citologia , Diferenciação Celular/fisiologia , Interleucinas/fisiologia , Osteoblastos/metabolismo , Osteoclastos/citologia , Fosfatase Ácida/metabolismo , Animais , Basófilos/citologia , Basófilos/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Osso e Ossos/patologia , Calcitriol/farmacologia , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Cultivadas , Eosinófilos/citologia , Eosinófilos/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/farmacologia , Isoenzimas/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Ligante RANK/genética , Ligante RANK/farmacologia , Receptores de Interleucina/genética , Células Estromais/citologia , Células Estromais/fisiologia , Fosfatase Ácida Resistente a TartaratoRESUMO
Although Wnt signaling in osteoblasts is of critical importance for the regulation of bone remodeling, it is not yet known which specific Wnt receptors of the Frizzled family are functionally relevant in this process. In this paper, we show that Fzd9 is induced upon osteoblast differentiation and that Fzd9(-/-) mice display low bone mass caused by impaired bone formation. Our analysis of Fzd9(-/-) primary osteoblasts demonstrated defects in matrix mineralization in spite of normal expression of established differentiation markers. In contrast, we observed a reduced expression of chemokines and interferon-regulated genes in Fzd9(-/-) osteoblasts. We also identified the ubiquitin-like modifier Isg15 as one potential downstream mediator of Fzd9 in these cells. Importantly, our molecular analysis further revealed that canonical Wnt signaling is not impaired in the absence of Fzd9, thus explaining the absence of a bone resorption phenotype. Collectively, our results reveal a previously unknown function of Fzd9 in osteoblasts, a finding that may have therapeutic implications for bone loss disorders.