Mr. Yi and Dr. H.-J. Kim contributed equally to this work.
Regulation of inflammatory responses and fibroblast-like synoviocyte apoptosis by calcineurin-binding protein 1 in mice with collagen-induced arthritis
Article first published online: 26 JUN 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 7, pages 2191–2200, July 2012
How to Cite
Yi, J.-K., Kim, H.-J., Yu, D.-H., Park, S.-J., Shin, M.-J., Yuh, H.-S., Bae, K.-B., Ji, Y.-R., Kim, N.-R., Park, S.-J., Kim, J.-Y., Lee, H.-S., Lee, S.-G., Yoon, D. H., Hyun, B.-H., Kim, W.-U. and Ryoo, Z.-Y. (2012), Regulation of inflammatory responses and fibroblast-like synoviocyte apoptosis by calcineurin-binding protein 1 in mice with collagen-induced arthritis. Arthritis & Rheumatism, 64: 2191–2200. doi: 10.1002/art.34398
- Issue published online: 26 JUN 2012
- Article first published online: 26 JUN 2012
- Accepted manuscript online: 24 JAN 2012 03:52PM EST
- Manuscript Accepted: 17 JAN 2012
- Manuscript Received: 12 APR 2011
- Korean Ministry for Health, Welfare and Family Affairs. Grant Number: Korea Healthcare Technology R&D Project grant A092258
- Korean Rural Development Administration. Grant Number: Next-Generation BioGreen 21 Program grant PJ008050
- Korean Ministry of Education, Science and Technology (Regional Core Research Program grant and Basic Science Research Program). Grant Number: 2010-0028076
- National Research Foundation of Korea
- Korea Science and Engineering Foundation. Grant Number: SRC program grant 2009-0063409
- Korean government
Calcineurin-binding protein 1 (CABIN-1) regulates calcineurin phosphatase activity as well as the activation, apoptosis, and inflammatory responses of fibroblast-like synoviocytes (FLS), which actively participate in the chronic inflammatory responses in rheumatoid arthritis (RA). However, the mechanism of action of CABIN-1 in FLS apoptosis is not clear. This study was undertaken to define the regulatory role of CABIN-1 in FLS from mice with collagen-induced arthritis (CIA).
Transgenic mice overexpressing human CABIN-1 in joint tissue under the control of a type II collagen promoter were generated. Expression of human CABIN-1 (hCABIN-1) in joints and FLS was determined by reverse transcription–polymerase chain reaction (RT-PCR) and Western blot analysis. The expression of cytokines, matrix metalloproteinases (MMPs), and apoptosis-related genes in FLS was determined by enzyme-linked immunosorbent assay, gelatin zymography, and RT-PCR, respectively. Joints were stained with hematoxylin and eosin and with tartrate-resistant acid phosphatase for histologic analysis.
Human CABIN-1–transgenic mice with CIA had less severe arthritis than wild-type mice with CIA, as assessed according to hind paw thickness and histologic features. The milder arthritis was accompanied by significantly enhanced apoptosis in transgenic mice, evidenced by a significantly greater number of TUNEL-positive cells in synovial tissue. Expression of inflammatory cytokines and MMPs in the transgenic mice with CIA was reduced, and they exhibited decreased Akt activation and increased expression of p53, caspase 3, caspase 9, and Bax.
Our findings demonstrate that hCABIN-1 plays a critical role in promoting apoptosis of FLS and in attenuating inflammation and cartilage and bone destruction in RA. These results help elucidate the pathogenic mechanisms of RA and suggest that CABIN-1 is a potential target for treatment of this disease.