p21-Mediated Regulation of IL-6 and MMP-1 in RA

描述（由申请人提供）：类风湿性关节炎（RA）是一种慢性炎症性和破坏性关节病变，导致发病率和死亡率增加。构成滑膜内膜的成纤维细胞（滑膜成纤维细胞）是一种与软骨和骨直接接触的薄膜，是导致RA发病的主要细胞之一。在RA中，滑膜成纤维细胞数量增加并产生促炎细胞因子和基质金属蛋白酶（MMPs），促进炎症和关节破坏。我们最近发现了细胞周期抑制剂p21在RA中的新作用，即p21不仅阻断细胞周期进程，还减少IL-6和MMP-1的合成。与骨关节炎滑膜成纤维细胞相比，RA中的p21表达降低。p21的恢复阻断了RA的细胞周期进程，抑制了IL-6和MMP-1的合成，但在非RA的滑膜成纤维细胞中没有作用。此外，恢复的p21降低了AP-1的DNA结合活性，AP-1是一种转录因子，在RA期间增加，是IL-6和MMP-1的已知诱导剂。与野生型细胞相比，p21缺失的滑膜成纤维细胞IL-6分泌增加100倍，IL-6和MMP-3 mRNA积累显著增加，AP-1 DNA结合活性增强。与Rb过表达（也会诱导细胞周期阻滞）相反，p21缺失的滑膜成纤维细胞中p21的恢复使IL-6和MMP-3恢复到野生型水平。根据我们的数据，我们假设p21通过抑制AP-1途径抑制正常关节中IL-6和MMP-1的转录。在RA关节中，p21通路存在缺陷，导致滑膜成纤维细胞增生，IL-6和MMP-1的合成增加。因此，可以通过恢复p21通路来治疗RA。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory and destructive arthropathy that results in increased morbidity and mortality. The fibroblasts that comprise the synovial lining (synovial fibroblasts), a thin membrane in direct contact with cartilage and bone, are one of the principal cells responsible for the pathogenesis of RA. In RA, the synovial fibroblasts increase in number and produce pro-inflammatory cytokines and matrix-metalloproteinases (MMPs) that promote inflammation and joint destruction. We recently discovered a novel role for the cell cycle inhibitor p21 in RA, namely that p21 not only blocks cell cycle progression, it also reduces the synthesis of IL-6 and MMP-1. p21 expression is reduced in RA compared to osteoarthritis synovial fibroblasts. Restoration of p21 blocks cell cycle progression and suppresses IL-6 and MMP-1 synthesis in RA but not in non-RA synovial fibroblasts. Additionally, restored p21 attenuates the DNA binding activity of AP-1, a transcription factor that is increased during RA and is a known inducer of IL-6 and MMP-1. p21-deficient synovial flbroblasts exhibit a 100-fold increase in IL-6 secretion, a marked increase in IL-6 and MMP-3 mRNA accumulation, and enhanced AP-1 DNA binding activity compared to wild-type cells. In contrast to Rb overexpression, which also induces cell cycle arrest, restoration of p21 in p21-deficient synovial fibroblasts returned IL-6 and MMP-3 to wild-type levels. Based on our data, we hypothesize that p21 suppresses IL-6 and MMP-1 transcription in the normal joint through the inhibition of the AP-1 pathway. In the RA joint, the p21 pathway is defective, resulting in proliferation of synovial fibroblasts and increased synthesis of IL-6 and MMP-1. Accordingly, RA may be treatable by restoring the p21 pathway.