Li Xiangli, Makarov Sergei S
Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17432-7. doi: 10.1073/pnas.0607939103. Epub 2006 Nov 6.
A hallmark of rheumatoid arthritis is the formation of an aggressive, tumor-like structure called pannus that erodes the joint. A major cellular component of the pannus is the fibroblast-like synoviocyte (FLS), whose morphology strikingly resembles that of a transformed cell, but underlying mechanisms of this "transformation" are not known. Here, using animal models of rheumatoid arthritis, we show that arthritic FLS contain a substantial (>30%) fraction of bone marrow-derived precursors that can differentiate in vitro into various mesenchymal cell types, but inflammation prevents the multilineage differentiation. We show that the transcription factor NF-kappaB plays the key role in the repression of osteogenic and adipogenic differentiation of arthritic FLS. Furthermore, we show that specific activation of NF-kappaB profoundly enhances proliferation, motility, and matrix-degrading activity of FLS. We thus propose that arthritic FLS are mesenchymal stem cells whose differentiation is arrested at early stages of differentiation by activation of NF-kappaB.
类风湿性关节炎的一个标志是形成一种侵袭性的、肿瘤样结构，称为血管翳，它会侵蚀关节。血管翳的主要细胞成分是成纤维细胞样滑膜细胞（FLS），其形态与转化细胞极为相似，但这种“转化”的潜在机制尚不清楚。在此，我们利用类风湿性关节炎动物模型表明，关节炎性FLS含有大量（>30%）骨髓来源的前体细胞，这些前体细胞在体外可分化为多种间充质细胞类型，但炎症会阻止多谱系分化。我们发现转录因子NF-κB在抑制关节炎性FLS的成骨和成脂分化中起关键作用。此外，我们还表明NF-κB的特异性激活能显著增强FLS的增殖、迁移和基质降解活性。因此，我们提出关节炎性FLS是间充质干细胞，其分化因NF-κB的激活而在分化早期停滞。
