A cell-cycle independent role for p21 in regulating synovial fibroblast migration in rheumatoid arthritis.
A cell-cycle independent role for p21 in regulating synovial fibroblast migration in rheumatoid arthritis.
复制标题
p21在调节类风湿关节炎中的滑膜成纤维细胞迁移中的独立作用。
DOI：
10.1186/ar1999
复制
发表时间：
2006
影响因子：
4.9
通讯作者：
Perlman, Harris
中科院分区：
文献类型：
--
作者：
Woods, James M;Klosowska, Karolina;Spoden, Darrin J;Stumbo, Nataliya G;Paige, Douglas J;Scatizzi, John C;Volin, Michael V;Rao, Malathi S;Perlman, Harris
类风湿性关节炎（RA）是一种以滑膜增生、软骨和骨破坏为特征的疾病。成纤维细胞样滑膜细胞（FLS）群体通过迁移到软骨和骨中对血管翳的发展至关重要。我们之前证明，RA滑液衬里中细胞周期抑制剂p21的表达显着减少，特别是在FLS中。本研究的目的是确定FLS中p21表达减少是否会改变这些细胞的迁移行为。从p21缺陷（p21（-/-））小鼠中分离FLS，并检查其生长和迁移。比较了p21（-/-）和野生型（WT）FLS在存在和不存在细胞周期抑制剂的情况下向RA滑液中发现的趋化因子迁移的情况。使用腺病毒感染完成p21表达的恢复。正如从细胞周期抑制剂的损失所预期的，p21（-/-）FLS比WT FLS生长更快。在检查向生物学相关RA滑液的迁移时，与WT细胞相比，p21（-/-）FLS显示迁移显著增加（3.1倍; p < 0.05）。此外，这种效应与细胞周期无关，因为阻断细胞周期的化学抑制剂对迁移没有影响。相反，p21需要抑制迁移，因为p21（-/-）FLS中p21表达的恢复逆转了这种作用。总之，这些数据表明，p21在正常FLS中起着新的作用，即抑制迁移。RA FLS中p21表达的缺失可能导致过度侵袭和随后的关节破坏。
Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and destruction of cartilage and bone. The fibroblast-like synoviocyte (FLS) population is central to the development of pannus by migrating into cartilage and bone. We demonstrated previously that expression of the cell cycle inhibitor p21 is significantly reduced in RA synovial lining, particularly in the FLS. The aim of this study was to determine whether reduced expression of p21 in FLS could alter the migratory behavior of these cells. FLS were isolated from mice deficient in p21 (p21(-/-)) and were examined with respect to growth and migration. p21(-/-) and wild-type (WT) FLS were compared with respect to migration towards chemoattractants found in RA synovial fluid in the presence and absence of cell cycle inhibitors. Restoration of p21 expression was accomplished using adenoviral infection. As anticipated from the loss of a cell cycle inhibitor, p21(-/-) FLS grow more rapidly than WT FLS. In examining migration towards biologically relevant RA synovial fluid, p21(-/-) FLS display a marked increase (3.1-fold; p < 0.05) in migration compared to WT cells. Moreover, this effect is independent of the cell cycle since chemical inhibitors that block the cell cycle have no effect on migration. In contrast, p21 is required to repress migration as restoration of p21 expression in p21(-/-) FLS reverses this effect. Taken together, these data suggest that p21 plays a novel role in normal FLS, namely to repress migration. Loss of p21 expression that occurs in RA FLS may contribute to excessive invasion and subsequent joint destruction.