Yang Nianlan, Baban Babak, Isales Carlos M, Shi Xing-Ming
Departments of Neuroscience & Regenerative Medicine, Augusta University, Augusta, GA, United States of America.
Departments of Oral Biology, Augusta University, Augusta, GA, United States of America.
PLoS One. 2017 Aug 3;12(8):e0181133. doi: 10.1371/journal.pone.0181133. eCollection 2017.
TNF-α plays a key role in the development of rheumatoid arthritis (RA) and inflammatory bone loss. Unfortunately, treatment of RA with anti-inflammatory glucocorticoids (GCs) also causes bone loss resulting in osteoporosis. Our previous studies showed that overexpression of glucocorticoid-induced leucine zipper (GILZ), a mediator of GC's anti-inflammatory effect, can enhance osteogenic differentiation in vitro and bone acquisition in vivo. To investigate whether GILZ could antagonize TNF-α-induced arthritic inflammation and protect bone in mice, we generated a TNF-α-GILZ double transgenic mouse line (TNF-GILZ Tg) by crossbreeding a TNF-α Tg mouse, which ubiquitously expresses human TNF-α, with a GILZ Tg mouse, which expresses mouse GILZ under the control of a 3.6kb rat type I collagen promoter fragment. Results showed that overexpression of GILZ in bone marrow mesenchymal stem/progenitor cells protected mice from TNF-α-induced inflammatory bone loss and improved bone integrity (TNF-GILZ double Tg vs. TNF-αTg, n = 12-15). However, mesenchymal cell lineage restricted GILZ expression had limited effects on TNF-α-induced arthritic inflammation as indicated by clinical scores and serum levels of inflammatory cytokines and chemokines.
肿瘤坏死因子-α（TNF-α）在类风湿性关节炎（RA）的发展以及炎症性骨质流失过程中发挥关键作用。遗憾的是，使用抗炎糖皮质激素（GCs）治疗RA也会导致骨质流失，进而引发骨质疏松。我们之前的研究表明，糖皮质激素诱导亮氨酸拉链（GILZ）作为GC抗炎作用的一种介质，其过表达能够在体外增强成骨分化，并在体内促进骨质生成。为了探究GILZ是否能够拮抗TNF-α诱导的小鼠关节炎炎症并保护骨骼，我们通过将广泛表达人TNF-α的TNF-α转基因小鼠与在3.6kb大鼠I型胶原启动子片段控制下表达小鼠GILZ的GILZ转基因小鼠杂交，培育出了TNF-α-GILZ双转基因小鼠品系（TNF-GILZ Tg）。结果显示，骨髓间充质干/祖细胞中GILZ的过表达保护小鼠免受TNF-α诱导的炎症性骨质流失，并改善了骨骼完整性（TNF-GILZ双转基因小鼠与TNF-α转基因小鼠相比，n = 12 - 15）。然而，如临床评分以及炎症细胞因子和趋化因子的血清水平所示，间充质细胞谱系受限的GILZ表达对TNF-α诱导的关节炎炎症影响有限。
