Laboratory of Experimental Rheumatology, Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, 350 Community Drive Room 1240, Manhasset, NY 11030, USA.
BMC Genomics. 2012 Dec 19;13:710. doi: 10.1186/1471-2164-13-710.
Cia5a is a locus on rat chromosome 10 that regulates disease severity and joint damage in two models of rheumatoid arthritis, collagen- and pristane-induced arthritis (PIA). In this study, we aimed to identify cellular and molecular processes regulated by Cia5a using microarray-based gene expression analysis of synovial tissues from MHC identical DA (severe erosive disease) and DA.F344(Cia5a) congenics (mild non-erosive disease) rats.
Synovial tissues from six DA and eight DA.F344(Cia5a) rats were analyzed 21 days after the induction of PIA using the Illumina RatRef-12 BeadChip (21,922 genes) and selected data confirmed with qPCR. There was a significantly increased expression of pro-inflammatory mediators such as Il1b (5-fold), Il18 (3.9-fold), Cxcl1 (10-fold), Cxcl13 (7.5-fold) and Ccl7 (7.9-fold), and proteases like Mmp3 (23-fold), Mmp9 (32-fold), Mmp14 (4.4-fold) and cathepsins in synovial tissues from DA, with reciprocally reduced levels in congenics. mRNA levels of 47 members of the Spleen Tyrosine Kinase (Syk) pathway were significantly increased in DA synovial tissues compared with DA.F344(Cia5a), and included Syk (5.4-fold), Syk-activating receptors and interacting proteins, and genes regulated by Syk such as NFkB, and NAPDH oxidase complex genes. Nuclear receptors (NR) such as Rxrg, Pparg and Rev-erba were increased in the protected congenics, and so was the anti-inflammatory NR-target gene Scd1 (54-fold increase). Tnn (72-fold decrease) was the gene most significantly increased in DA.
Analyses of gene expression in synovial tissues revealed that the arthritis severity locus Cia5a regulates the expression of key mediators of inflammation and joint damage, as well as the expression of members of the Syk pathway. This expression pattern correlates with disease severity and joint damage and along with the gene accounting for Cia5a could become a useful biomarker to identify patients at increased risk for severe and erosive disease. The identification of the gene accounting for Cia5a has the potential to generate a new and important target for therapy and prognosis.
Cia5a 是大鼠 10 号染色体上的一个基因座，可调节两种类风湿关节炎模型（胶原诱导性关节炎和 pristane 诱导性关节炎）中的疾病严重程度和关节损伤。在这项研究中，我们旨在使用基于微阵列的基因表达分析，鉴定由 Cia5a 调控的滑膜组织中的细胞和分子过程，这些滑膜组织来自 MHC 相同的 DA（严重侵蚀性疾病）和 DA.F344（Cia5a）同系物（轻度非侵蚀性疾病）大鼠。
在 pristane 诱导关节炎 21 天后，使用 Illumina RatRef-12 BeadChip（21,922 个基因）分析了来自 6 只 DA 和 8 只 DA.F344（Cia5a）大鼠的滑膜组织，并使用 qPCR 对选定的数据进行了确认。在 DA 的滑膜组织中，促炎介质如 Il1b（5 倍）、Il18（3.9 倍）、Cxcl1（10 倍）、Cxcl13（7.5 倍）和 Ccl7（7.9 倍）以及蛋白酶如 Mmp3（23 倍）、Mmp9（32 倍）、Mmp14（4.4 倍）和组织蛋白酶的表达显著增加，而同系物中的表达则相反降低。与 DA.F344（Cia5a）相比，DA 滑膜组织中 Spleen Tyrosine Kinase（Syk）通路的 47 个成员的 mRNA 水平显著升高，包括 Syk（5.4 倍）、Syk 激活受体和相互作用蛋白，以及由 Syk 调节的基因，如 NFkB 和 NADPH 氧化酶复合物基因。核受体（NR）如 Rxrg、Pparg 和 Rev-erba 在保护性同系物中增加，抗炎性 NR 靶基因 Scd1（增加 54 倍）也是如此。Tnn（72 倍减少）是 DA 中增加最多的基因。
对滑膜组织中基因表达的分析表明，关节炎严重程度基因座 Cia5a 调节炎症和关节损伤的关键介质的表达，以及 Syk 通路成员的表达。这种表达模式与疾病严重程度和关节损伤相关，并且与负责 Cia5a 的基因相关，可能成为识别严重和侵蚀性疾病风险增加的患者的有用生物标志物。负责 Cia5a 的基因的鉴定有可能成为新的和重要的治疗和预后靶点。
