Laboratory of Experimental Rheumatology, Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
Physiol Genomics. 2013 Jul 2;45(13):552-64. doi: 10.1152/physiolgenomics.00029.2013. Epub 2013 May 21.
Cia4 is a locus on rat chromosome 7 that regulates disease severity and joint damage in models of rheumatoid arthritis, including pristane-induced arthritis (PIA). To identify molecular processes regulated by Cia4, synovial tissues from MHC-identical DA (severe erosive) and DA.F344(Cia4) congenics (mild nonerosive) rats were collected at preclinical and recent onset stages following the induction of PIA and analyzed for gene expression levels. Il6 levels were significantly higher in DA compared with congenics on day 10 (135-fold) after PIA induction (preclinical stage) and remained increased on days 14 (47.7-fold) and 18 (29.41-fold). Il6 increased before Il1b suggesting that Il6 could be driving Il1b expression and early synovial inflammation; 187 genes had significantly different expression levels and included inflammatory mediators increased in DA such Slpi (10.94-fold), Ccl7 (5.17-fold), and Litaf (2.09-fold). Syk or NF-κB activating and interacting genes, including Cd74 Ccl21, were increased in DA; 59 genes implicated in cancer-related phenotypes were increased in DA. Genes involved in cell metabolism, transport across membranes, and tissue protection such as Dgat1, Dhcr7, and Slc1a1 were increased in DA.F344(Cia4) congenics; 21 genes differentially expressed or expressed in only one of the strains were located within the Cia4 interval and could be the gene accounting for the arthritis effect. In conclusion, the Cia4 interval contains at least one new arthritis gene that regulates early Il6, Il1b expression, and other inflammatory mediators. This gene regulates the expression of cancer genes that could mediate the development of synovial hyperplasia and invasion, and cartilage and bone destruction.
Cia4 是大鼠染色体 7 上的一个基因座，可调节类风湿关节炎模型（包括 pristane 诱导的关节炎 [PIA]）中的疾病严重程度和关节损伤。为了鉴定由 Cia4 调节的分子过程，在 PIA 诱导后临床前和近期发病阶段，从 MHC 相同的 DA（严重侵蚀性）和 DA.F344（Cia4）同系物（轻度非侵蚀性）大鼠的滑膜组织中收集，并分析基因表达水平。在 PIA 诱导后 10 天（临床前阶段），DA 中的 Il6 水平明显高于同系物（135 倍），并且在第 14 天（47.7 倍）和第 18 天（29.41 倍）仍保持升高。Il6 在 Il1b 之前升高表明 Il6 可能驱动 Il1b 表达和早期滑膜炎症；有 187 个基因的表达水平有显著差异，包括在 DA 中增加的炎症介质，如 Slpi（10.94 倍）、Ccl7（5.17 倍）和 Litaf（2.09 倍）。DA 中增加了 Syk 或 NF-κB 激活和相互作用的基因，包括 Cd74 和 Ccl21；在 DA 中增加了 59 个与癌症相关表型相关的基因。参与细胞代谢、跨膜运输和组织保护的基因，如 Dgat1、Dhcr7 和 Slc1a1，在 DA.F344（Cia4）同系物中增加；21 个在一个或两个品系中差异表达或表达的基因位于 Cia4 区间内，可能是导致关节炎效应的基因。总之，Cia4 区间至少包含一个新的关节炎基因，可调节早期 Il6、Il1b 表达和其他炎症介质。该基因调节癌症基因的表达，可能介导滑膜增生和侵袭以及软骨和骨破坏的发生。
