Abstract
Bone marrow CD34+ cells from rheumatoid arthritis (RA) patients have abnormal capacities to respond to tumor necrosis factor (TNF)-α and to differentiate into fibroblast-like cells producing matrix metalloproteinase (MMP)-1. We explored the expression of mRNA for nuclear factor (NF)κB in RA bone marrow CD34+ cells to delineate the mechanism for their abnormal responses to TNF-α. CD34+ cells were purified from bone marrow samples obtained from 49 RA patients and 31 osteoarthritis (OA) patients during joint operations via aspiration from the iliac crest. The mRNAs for NFκB1 (p50), NFκB2 (p52) and RelA (p65) were examined by quantitative RT-PCR. The expression of NFκB1 mRNA in bone marrow CD34+ cells was significantly higher in RA than in OA, whereas there was no significant difference in the expression of mRNA for NFκB2 and RelA. The expression of NFκB1 mRNA was not correlated with serum C-reactive protein or with the treatment with methotrexate or oral steroid. Silencing of NFκB1 by small interfering RNA abrogated the capacity of RA bone marrow CD34+ cells to differentiate into fibroblast-like cells and to produce MMP-1 and vascular endothelial growth factor upon stimulation with stem cell factor, granulocyte-macrophage colony stimulating factor and TNF-α without influencing their viability and capacity to produce β2-microglobulin. These results indicate that the enhanced expression of NFκB1 mRNA in bone marrow CD34+ cells plays a pivotal role in their abnormal responses to TNF-α and, thus, in the pathogenesis of RA.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by hyperplasia of synovial lining cells, consisting of macrophage-like type A synoviocytes and fibroblast-like type B synoviocytes [1]
These results indicate that the enhanced expression of NFκB1 mRNA in bone marrow CD34+ cells plays a pivotal role in their abnormal responses to tumor necrosis factor (TNF)-α and, in the pathogenesis of rheumatoid arthritis (RA)
We have recently demonstrated that bone marrow CD34+ cells from RA patients have abnormal capacities to respond to tumor necrosis factor (TNF)-α and to differentiate into fibroblast-like cells producing matrix metalloproteinase (MMP)-1, suggesting that bone marrow CD34+ progenitor cells might generate type B synoviocytes and could play an important role in the pathogenesis of RA [2]
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by hyperplasia of synovial lining cells, consisting of macrophage-like type A synoviocytes and fibroblast-like type B synoviocytes [1]. Type B synoviocytes, which are called fibroblast-like synoviocytes, have the morphological appearance of fibroblasts as well as the capacity to produce and secrete a variety of factors, including proteoglycans, cytokines, arachidonic acid metabolites, and matrix metalloproteinases (MMPs), that lead to the destruction of joints [1]. TNF-α is one of the first triggers to be found effective for the activation of nuclear factor (NF)κB in RA synovium [3] This β2MG = β2-microglobulin; ELISA = enzyme-kinked immunosorbent assay; GM-CSF = granulocyte-macrophage colony stimulating factor; HSCT = hematopoietic stem cell transplantation; MFI = mean fluorescence intensity; MMP = matrix metalloproteinase; MTX = methotrexate; NFκB = nuclear factor kappa B; OA = osteoarthritis; PCR = polymerase chain reaction; PE = phychoerythrin; RA = rheumatoid arthritis; SCF = stem cell factor; siRNA
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