Identification of two new arthritis severity loci that regulate levels of autoantibodies, interleukin-1β, and joint damage in pristane- and collagen-induced arthritis.
Identification of two new arthritis severity loci that regulate levels of autoantibodies, interleukin-1β, and joint damage in pristane- and collagen-induced arthritis.
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DOI：
10.1002/art.33468
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发表时间：
2012-05
影响因子：
--
通讯作者：
Gulko, Percio S.
中科院分区：
文献类型：
--
作者：
Brenner, Max;Laragione, Teresina;Shah, Anish;Mello, Adriana;Remmers, Elaine F.;Wilder, Ronald L.;Gulko, Percio S.
Cia 3是大鼠4号染色体上的一个位点，其调节胶原和降植烷诱导的关节炎（CIA和PIA）的严重程度和关节损伤。本研究旨在完善Cia 3基因的基因识别间隔，并深入了解其作用模式。F344（Cia 3）亚同源菌株产生并在PIA和CIA中研究。测量针对II型胶原蛋白的抗体（同种抗体和自身抗体）的水平。在诱导PIA（慢性期）后32天收集关节和滑膜组织用于组织学和用于IL-1β和基质金属蛋白酶（MMP）的qPCR。三个亚同源共享着丝粒Cia 3d间隔的保护，而两个亚同源共享端粒Cia 3g间隔，不与Cia 3d重叠，也受到保护，发展显着较轻的CIA和PIA。与PIA同源的DA.F344（Cia 3）和DA.F344（Cia 3d）保留了正常的关节结构，而DA大鼠具有明显的滑膜增生、血管生成、炎性浸润、骨或软骨侵蚀。与DA相比，DA.F344（Cia 3d）和DA.F344（Cia 3g）菌株的IL-1β（5倍）、MMP-1（主要在DA中表达）、MMP-3（79倍）和MMP-14（21倍）的滑膜水平显著降低，并且针对II型胶原的致病性自身抗体水平降低。这些基因座在两种不同的RA模型中调节致病过程，这些基因的鉴定有可能为旨在降低疾病严重程度和关节损伤的治疗产生新的靶点，并为RA的治疗提供新的靶点。
Cia3 is a locus on rat chromosome 4 that regulates severity and joint damage in collagen and pristane-induced arthritis (CIA and PIA). This study aimed to refine the Cia3 gene-containing interval towards gene identification and obtain insights into its mode of action. Five DA.F344(Cia3) subcongenic strains were generated and studied in PIA and CIA. Levels of antibodies against type II collagen (both allo- and autoantibodies) were measured. Joints and synovial tissues were collected 32 days after the induction of PIA (chronic stage) for histology and qPCR for IL-1β and matrix metalloproteases (MMPs). Three subcongenics sharing the centromeric Cia3d interval were protected, while two subcongenics sharing the telomeric Cia3g interval, which did not overlap with Cia3d, were also protected, developing significantly less severe CIA and PIA. DA.F344(Cia3) and DA.F344(Cia3d) congenics with PIA preserved a normal joint architecture, while DA rats had pronounced synovial hyperplasia, angiogenesis, inflammatory infiltration, bone or cartilage erosions. DA.F344(Cia3d) and DA.F344(Cia3g) strains had significantly lower synovial levels of IL-1β (5-fold), MMP-1 (expressed predominantly in DA), MMP-3 (79-fold) and MMP-14 (21-fold) and reduced levels of pathogenic autoantibodies against type II collagen, compared with DA. We have identified two new arthritis severity and articular damage loci within Cia3. These loci regulate pathogenic processes in two different models of RA, and the identification of these genes has the potential to generate new targets for therapies aimed at reducing disease severity and articular damage, and for prognostication in RA.
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影响因子：
15.9
作者：
DECHANET, J;MERVILLE, P;MIOSSEC, P
通讯作者：
MIOSSEC, P
影响因子：
158.5
作者：
Edwards, JCW;Szczepanski, L;Shaw, T
通讯作者：
Shaw, T
影响因子：
15.3
作者：
FAVA, RA;OLSEN, NJ;TOWNES, AS
通讯作者：
TOWNES, AS
影响因子：
12.8
作者：
Kleinau S;Erlandsson H;Holmdahl R;Klareskog L
通讯作者：
Klareskog L
影响因子：
--
作者：
Brenner, M;Meng, HC;Gulko, NS
通讯作者：
Gulko, NS