St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia.
Genes Immun. 2013 Jul-Aug;14(5):336-45. doi: 10.1038/gene.2013.29. Epub 2013 May 23.
Receptor activator of nuclear factor-kappaB-ligand (RANKL), encoded by the gene TNFSF11, is required for osteoclastogenesis, and its expression is upregulated in pathologic bone loss. Transcript variants of TNFSF11 messenger RNA (mRNA) have been described that encode a membrane-bound and a putative secreted form of RANKL. We identify a TNFSF11 transcript variant that extends the originally identified transcript encoding secreted RANKL. We demonstrate that this TNFSF11 transcript variant is expressed by the human osteosarcoma cell line, Saos-2, and by both primary human T cells and Jurkat T cells. Of relevance to the production of RANKL in pathologic bone loss, expression of this secreted TNFSF11 transcript is upregulated in Jurkat T cells and primary human T cells upon activation. Furthermore, this transcript can be translated and secreted in Jurkat T cells in vitro and is able to support osteoclast differentiation. Our data highlight the complexity of the TNFSF11 genomic locus, and demonstrate the potential for the expression of alternate mRNA transcripts encoding membrane-bound and secreted forms of RANKL. Implications of alternate mRNA transcripts encoding different RANKL protein isoforms should be carefully considered and specifically examined in future studies, particularly those implicating RANKL in pathologic bone loss.
核因子-κB 受体激活物配体（RANKL），由基因 TNFSF11 编码，是破骨细胞形成所必需的，其表达在病理性骨丢失中上调。已经描述了 TNFSF11 信使 RNA（mRNA）的转录变体，这些转录变体编码 RANKL 的膜结合和假定分泌形式。我们鉴定了一个 TNFSF11 转录变体，它扩展了最初鉴定的编码分泌型 RANKL 的转录本。我们证明，这种 TNFSF11 转录变体在人骨肉瘤细胞系 Saos-2 中以及在原代人 T 细胞和 Jurkat T 细胞中表达。与病理性骨丢失中 RANKL 的产生相关，在 Jurkat T 细胞和原代人 T 细胞中，这种分泌型 TNFSF11 转录本在激活时上调。此外，这种转录本可以在体外 Jurkat T 细胞中翻译和分泌，并能够支持破骨细胞分化。我们的数据强调了 TNFSF11 基因组位点的复杂性，并证明了表达膜结合和分泌形式的 RANKL 的替代 mRNA 转录本的潜力。在未来的研究中，特别是那些涉及 RANKL 在病理性骨丢失中的研究中，应仔细考虑并特别检查编码不同 RANKL 蛋白同工型的替代 mRNA 转录本的含义。
