An essential role of NF-kappaB in the "tumor-like" phenotype of arthritic synoviocytes.
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.
Li
Xiangli
X
Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Makarov
Sergei S
SS
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D017746:Joint Capsule / Q000378:metabolism* / Q000473:pathology*; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype; D051381:Rats; D015996:Survival Rate
D016207:Cytokines; D016328:NF-kappa B; D053509:Matrix Metalloproteinase 13