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首页> 外文期刊>Nucleus >Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes
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Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes

机译：金刚砂-Dreifuss肌营养不良症中TGFβ2血清水平升高：对肌细胞和肌腱细胞分化和成纤维过程的影响

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Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.
机译：在LMNA基因突变引起的罕见疾病中，Emery-Dreifuss型肌肉营养不良2型和Limb-Girdle型肌肉营养不良1B的特征是肌肉无力和消瘦，关节挛缩，带有传导系统疾病的心肌病。这些病理的循环生物标志物尚未确定。在这里，我们分析了受这些肌肉型多发性神经病影响的一组患者的分泌组，以试图确定一个共同的特征。多重细胞因子测定显示，在绝大多数接受检查的患者中，转化生长因子β2（TGFβ2）和白细胞介素17血清水平持续升高，而在患者亚组中白细胞介素6和碱性成纤维细胞生长因子发生改变。在由患者活检组织建立的成纤维细胞和成肌细胞培养物中，以及在人类中引起人Emery-Dreifuss肌营养不良的携带H222P Lmna突变的小鼠的血清中，TGFβ2的水平也增加了。患者血清和成纤维细胞条件培养基均能激活正常人成肌细胞和肌腱细胞中TGFβ2依赖的成纤维程序，并抑制成肌细胞分化。与这些结果一致，TGFβ2中和抗体避免了纤维化标记物活化和肌生成障碍。还确定了在Laminopathic细胞中细胞内在的TGFβ2依赖性机制，其中TGFβ2激活了AKT / mTOR磷酸化。这些数据表明，TGFβ2促成2型金刚砂-Dreifuss型肌营养不良症和1L-腰带型肌营养不良症的发病机理，并可以认为是这些疾病的潜在生物标志物。此外，肌腱细胞中TGFβ2致病作用的证据为了解肌肉性椎间皮病关节挛缩的发生提供了第一个力学见解。

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