Intraarticular gene transfer of SPRY2 suppresses adjuvant-induced arthritis in rats.
AKT and ERK pathways have been implicated as therapeutic targets for human rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) inhibition, and thus RA treatment. Sprouty2 (SPRY2) has been known as a tumor suppressor by blocking both ERK and AKT signaling cascades. Whether SPRY2 can function as a suppressor of tumor-like inflammatory FLS and RA through negatively regulating AKT and ERK activation has not been reported. The purpose of this study was to determine whether SPRY2 might have antiarthritic effects in experimental animal model of RA. We first determined that expression of SPRY2 mRNA was decreased in FLS from patients with RA compared with patients with osteoarthritis (OA). Further studies demonstrated that intraarticular gene transfer with AdSPRY2, the recombinant adenovirus containing SPRY2 complementary DNA, resulted in a significant suppression of rat adjuvant-induced arthritis (AIA) compared with the control AdGFP, the adenoviral vector encoding green fluorescent protein, as reflected in both clinical and histological observations. AdSPRY2 suppressed the production of proinflammatory cytokines and matrix metalloproteinases (MMPs), and the activation of ERK and AKT signals in AIA ankle joints. These results suggest that using SPRY2 to block the AKT and ERK pathways effectively reduces the inflammatory responses and arthritic progression in AIA. Thus, the development of an immunoregulatory strategy based on SPRY2 may therefore have therapeutic potential in the treatment of RA.
Department of Translational Medicine, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Haidian District, Beijing, 100850, China, zhangweiyh@126.com.
Wei
W
Zhang
Jingying
J
Zhu
Zhiyan
Z
Du
Jiyun
J
Yu
Yuanji
Y
Xu
Fang
F
Wang
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy*; D016207:Cytokines / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D020935:MAP Kinase Signaling System; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D051381:Rats; D016896:Treatment Outcome
D016207:Cytokines; D009419:Nerve Tissue Proteins; C404992:Spry2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D020782:Matrix Metalloproteinases