PDF(Pubmed)
Abstract：
Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gαs and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gαs activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gαs activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.
摘要：
纤维发育不良（FD）是一种马赛克骨骼疾病，由编码Gαs的GNAS的体细胞激活变体引起，并导致骨髓基质细胞（BMSC）中过度的环磷酸腺苷信号传导。Gαs激活在BMSC转录组中的作用及其如何影响FD病变微环境尚不清楚。我们分析了在BMSC转录组和分泌组中由Gαs激活诱导的变化。FD患者和健康志愿者培养的BMSCs差异基因表达的RNAseq分析，从FD的诱导型小鼠模型中，被执行，并将两个模型的转录组图谱结合起来，以构建一个稳健的FDBMSC遗传签名。与Gα激活相关的途径，细胞因子信号，并鉴定了细胞外基质沉积。为了评估FD发病机制中几种关键分泌因子的调节，在培养基中测量细胞因子和其他因子.还从FD患者的血浆样本中筛选了细胞因子，几种细胞因子与其疾病负担评分呈正相关，以及彼此和骨转换标记，被发现了。这些数据支持促炎，FDBMSCs的促破骨细胞行为，并指出几种细胞因子和其他分泌因子作为FD的可能治疗靶标和/或循环生物标志物。
