한빛사논문
- 조회3,553
Abstract
Seung-Ah Yoo1, Sungyong You3, Hyung-Ju Yoon1, Dong-Ho Kim1, Hyun-Sook Kim4, Kyungho Lee5, Jin Hee Ahn6, Daehee Hwang3, Amy S. Lee7, Ki-Jo Kim1,2, Yune-Jung Park1,2, Chul-Soo Cho1,2, and Wan-Uk Kim1,2,*
1Research Institute of Immunobiology, Catholic Research Institute of Medical Science and 2Department of Internal Medicine, Catholic University of Korea, Seoul 137-701, South Korea
3School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, South Korea
4Department of Internal Medicine, Chosun University School of Medicine, Gwangju 501-759, South Korea
5Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, South Korea
6Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, South Korea
7Department of Biochemistry and Molecular Biology, University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033
*CORRESPONDENCE : Wan-Uk Kim
Abstract
An accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we found that ER stress-associated gene signatures were highly expressed in rheumatoid arthritis (RA) synoviums and synovial cells. Proinflammatory cytokines, such as TNF and IL-1β, increased the expression of GRP78/BiP, a representative ER chaperone, in RA synoviocytes. RA synoviocytes expressed higher levels of GRP78 than osteoarthritis (OA) synoviocytes when stimulated by thapsigargin or proinflammatory cytokines. Down-regulation of Grp78 transcripts increased the apoptosis of RA synoviocytes while abolishing TNF- or TGF-β-induced synoviocyte proliferation and cyclin D1 up-regulation. Conversely, overexpression of the Grp78 gene prevented synoviocyte apoptosis. Moreover, Grp78 small interfering RNA inhibited VEGF165-induced angiogenesis in vitro and also significantly impeded synoviocyte proliferation and angiogenesis in Matrigel implants engrafted into immunodeficient mice. Additionally, repeated intraarticular injections of BiP-inducible factor X, a selective GRP78 inducer, increased synoviocyte proliferation and angiogenesis in the joints of mice with experimental OA. In contrast, mice with Grp78 haploinsufficiency exhibited the suppression of experimentally induced arthritis and developed a limited degree of synovial proliferation and angiogenesis. In summary, this study shows that the ER chaperone GRP78 is crucial for synoviocyte proliferation and angiogenesis, the pathological hallmark of RA.
논문정보
- Research article
- 2012년 03월 (BRIC 등록일 )
- 국내(교신)+국외 연구진
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