Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes.
Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes.
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DOI：
10.1080/19491034.2018.1467722
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发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Lattanzi G
中科院分区：
文献类型：
--
作者：
Bernasconi P;Carboni N;Ricci G;Siciliano G;Politano L;Maggi L;Mongini T;Vercelli L;Rodolico C;Biagini E;Boriani G;Ruggiero L;Santoro L;Schena E;Prencipe S;Evangelisti C;Pegoraro E;Morandi L;Columbaro M;Lanzuolo C;Sabatelli P;Cavalcante P;Cappelletti C;Bonne G;Muchir A;Lattanzi G
在由LMNA基因突变引起的罕见疾病中，Emery-Dreifuss肌营养不良症2型和肢带肌营养不良症1B以肌无力和消瘦、关节挛缩、心肌病伴传导系统障碍为特征。尚未确定这些病理的循环生物标志物。在这里，我们分析了一组受这些肌层蛋白病影响的患者的分泌组，试图确定一个共同的签名。多重细胞因子检测显示，绝大多数受检患者血清转化生长因子β 2（TGF β2）和白细胞介素17水平持续升高，而白细胞介素6和碱性成纤维细胞生长因子在患者亚组中发生改变。在从患者活检建立的成纤维细胞和成肌细胞培养物中，以及在携带导致人类Emery-Dreifuss肌营养不良的H222 P Lmna突变的小鼠的血清中，TGF β2的水平也增加。患者血清和成纤维细胞条件培养基均激活正常人成肌细胞和肌腱细胞中的TGF β2依赖性纤维化程序，并抑制成肌细胞分化。与这些结果一致，TGF β2中和抗体避免了纤维化标志物激活和肌生成损伤。在核纤层病细胞中也确定了细胞内在的TGF β2依赖性机制，其中TGF β2激活AKT/mTOR磷酸化。这些数据表明，TGF β2有助于Emery-Dreifuss肌营养不良2型和肢带肌营养不良1B型的发病机制，可以被认为是这些疾病的潜在生物标志物。此外，TGF β2在腱细胞中的致病作用的证据提供了第一个在肌层蛋白病中关节挛缩发生的机制性见解。
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.
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影响因子：
2.4
作者：
Brown JP;Finley VG;Kuo CK
通讯作者：
Kuo CK
影响因子：
12.4
作者：
通讯作者：
--
DOI：
10.1002/jbmr.3199
发表时间：
2017-09
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Asahara H;Inui M;Lotz MK
通讯作者：
Lotz MK
影响因子：
17.1
作者：
Biressi S;Miyabara EH;Gopinath SD;Carlig PM;Rando TA
通讯作者：
Rando TA
影响因子：
3.5
作者：
Chatzifrangkeskou, Maria;Le Dour, Caroline;Muchir, Antoine
通讯作者：
Muchir, Antoine