[Disproportionately increased incidence of proximal femoral fractures in a level one trauma center : Epidemiological analysis from 2016 to 2022]. / Überproportional angestiegene Inzidenz proximaler Femurfrakturen in einem Level-One-Traumazentrum : Epidemiologische Analyse von 2016 bis 2022.

BACKGROUND: Proximal femoral fractures represent the most frequent fracture entity in Germany accounting for more than 20% of all fractures. According to a decision of the Federal Joint Committee from 2019, proximal femoral fractures also have to be surgically treated within 24 h. In order to quantify a subjectively perceived increase in workload in trauma surgery at a supraregional trauma center, a retrospective analysis of the number of surgically treated proximal femoral fractures was performed. Proximal femoral fractures were chosen due to their high incidence and homogeneous treatment. METHODS: Using ICD-10 codes, all surgically treated proximal femoral fractures from 2016 to 2022, including the patient's zip code, were retrieved from the database of the trauma center. RESULTS: The number of surgically treated proximal femoral fractures doubled from 2016 to 2022. The highest increase (60%) was recorded from 2020 to 2022. Heat maps show an increase in the catchment area radius as well. CONCLUSION: When compared (inter)nationally, a disproportionate increase in the amount of surgically treated proximal femoral fractures was recorded at the trauma center studied. The increase of the catchment area radius and the number of patients treated in the urban area show that less and less hospitals participate in emergency treatment. Possible explanations are a lack of resources aggravated by the recent COVID-19 pandemic and a lack of qualified personnel, interface problems between the federal states or the strict requirements of the Federal Joint Committee in the treatment of proximal femoral fractures. It must be assumed that there is a clearly increased workload for all professions involved in the trauma center investigated, although the infrastructure has remained unchanged.

Cytokine Interferon-γ suppresses the function of capsule myofibroblasts and induces cell apoptosis.

Myofibroblasts (MFs), a contractile subset of fibroblasts, play a pivotal role in physiological wound healing and in the development of many fibroconnective disorders. The complex cytokine network regulating the function of MFs in joint stiffness is still poorly understood. In this in vitro study, we investigated the effect of the cytokine Interferon-gamma (IFN-γ) on MFs isolated from human joint capsules. MFs were cultivated either in the presence of increasing concentrations of IFN-γ alone or in combination with IFN-γ neutralizing antibodies. Cell viability, cytotoxicity, apoptosis, and mRNA gene expression of the MF markers alpha-smooth muscle actin (α-SMA) and collagen type I were analyzed in MF cultures. Contraction potential was analyzed in an established collagen gel contraction assay simulating the extracellular matrix. Using immunofluorescence staining, we could verify that MFs express IFN-γ-receptor (R)-1 on their membrane. IFN-γ decreased MF viability and significantly elevated the apoptosis rate in a dose-dependent manner. IFN-γ down-regulated α-SMA and collagen type I mRNA expression which was associated with a diminished MF mediated contraction of the gel matrices. These effects were suppressed by simultaneous treatment of cells with a neutralizing IFN-γ antibody. Our experiments confirm the hypothesis that the cytokine IFN-γ is a crucial component of the regulatory network of capsule MFs. IFN-γ notably influences the ability of MFs to contract collagen matrices by suppressing α-SMA gene expression. IFN-γ is toxic for MFs in high concentrations and may negatively regulate the number of pro-fibrotic MFs during the healing process via induction of cell apoptosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2524-2533, 2017.

Influence of the anti-inflammatory cytokine interleukin-4 on human joint capsule myofibroblasts.

Post-traumatic joint contracture was reported to be associated with elevated numbers of contractile myofibroblasts (MFs) in the healing capsule. During the physiological healing process, the number of MFs declines; however, in fibroconnective disorders, MFs persist. The manifold interaction of the cytokines regulating the appearance and persistence of MFs in the pathogenesis of joint contracture remains to be elucidated. The objective of our current study was to analyze the impact of the anti-inflammatory cytokine interleukin (IL)-4 on functional behavior of MFs. Cells were isolated from human joint capsule specimens and challenged with three different concentrations of IL-4 with or without its neutralizing antibody. MF viability, contractile properties, and the gene expression of both alpha-smooth muscle actin (α-SMA) and collagen type I were examined. Immunofluorescence staining revealed the presence of IL-4 receptor (R)-alpha (α) on the membrane of cultured MFs. The cytokine IL-4 promoted MF viability and enhanced MF modulated contraction of collagen gels. Moreover, IL-4 intervened in gene expression by up-regulation of α-SMA and collagen type I mRNA. These effects could be specifically lowered by the neutralizing IL-4 antibody. On the basis of our findings we conclude that the anti-inflammatory cytokine IL-4 specifically regulates viability and the contractile properties of MFs via up-regulating the gene expression of α-SMA and collagen type I. IL-4 may be a helpful target in developing anti-fibrotic therapeutics for post-traumatic joint contracture in human. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1290-1298, 2017.

Inhibition of Contractile Function in Human Joint Capsule Myofibroblasts by Targeting the TGF-ß1 and PDGF Pathways.

BACKGROUND: Contractile myofibroblasts (MFs) accumulate in the joint capsules of patients suffering from posttraumatic joint stiffness. MF activation is controlled by a complex local network of growth factors and cytokines, ending in the increased production of extracellular matrix components followed by soft tissue contracture. Despite the tremendous growth of knowledge in this field, inconsistencies remain in practice and prevention. METHODS AND FINDINGS: In this in vitro study, we isolated and cultured alpha-smooth muscle actin (α-SMA) positive human joint capsule MFs from biopsy specimens and investigated the effect of profibrotic and antifibrotic agents on MF function. Both TGF-ß1 and PDGF significantly induced proliferation and increased extracellular matrix contraction in an established 3D collagen gel contraction model. Furthermore, both growth factors induced α-SMA and collagen type I gene expression in MFs. TGF-ß1 down-regulated TGF-ß1 and TGF-ß receptor (R) 1 and receptor (R) 2 gene expression, while PDGF selectively down-regulated TGF-ß receptor 2 gene expression. These effects were blocked by suramin. Interestingly, the anti-oxidant agent superoxide dismutase (SOD) blocked TGF-ß1 induced proliferation and collagen gel contraction without modulating the gene expression of α-SMA, collagen type I, TGF-ß1, TGF-ß R1 and TGF-ß R2. CONCLUSIONS: Our results provide evidence that targeting the TGF-ß1 and PDGF pathways in human joint capsule MFs affects their contractile function. TGF-ß1 may modulate MF function in the joint capsule not only via the receptor signalling pathway but also by regulating the production of profibrotic reactive oxygen species (ROS). In particular, anti-oxidant agents could offer promising options in developing strategies for the prevention and treatment of posttraumatic joint stiffness in humans.

The effect of the pro-inflammatory cytokine tumor necrosis factor-alpha on human joint capsule myofibroblasts.

INTRODUCTION: Previous studies have shown that the number of myoblastically differentiated fibroblasts known as myofibroblasts (MFs) is significantly increased in stiff joint capsules, indicating their crucial role in the pathogenesis of post-traumatic joint stiffness. Although the mode of MFs' function has been well defined for different diseases associated with tissue fibrosis, the underlying mechanisms of their regulation in the pathogenesis of post-traumatic joint capsule contracture are largely unknown. METHODS: In this study, we examined the impact of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on cellular functions of human joint capsule MFs. MFs were challenged with different concentrations of TNF-alpha with or without both its specifically inactivating antibody infliximab (IFX) and cyclooxygenase-2 (COX2) inhibitor diclofenac. Cell proliferation, gene expression of both alpha-smooth muscle actin (alpha-SMA) and collagen type I, the synthesis of prostaglandin derivates E2, F1A, and F2A, as well as the ability to contract the extracellular matrix were assayed in monolayers and in a three-dimensional collagen gel contraction model. The alpha-SMA and COX2 protein expressions were evaluated by immunofluorescence staining and Western blot analysis. RESULTS: The results indicate that TNF-alpha promotes cell viability and proliferation of MFs, but significantly inhibits the contraction of the extracellular matrix in a dose-dependent manner. This effect was associated with downregulation of alpha-SMA and collagen type I by TNF-alpha application. Furthermore, we found a significant time-dependent upregulation of prostaglandin E2 synthesis upon TNF-alpha treatment. The effect of TNF-alpha on COX2-positive MFs could be specifically prevented by IFX and partially reduced by the COX2 inhibitor diclofenac. CONCLUSIONS: Our results provide evidence that TNF-alpha specifically modulates the function of MFs through regulation of prostaglandin E2 synthesis and therefore may play a crucial role in the pathogenesis of joint capsule contractures.