Regulation of inflammatory responses and fibroblast-like synoviocyte apoptosis by calcineurin-binding protein 1 in mice with collagen-induced arthritis
| Autor: | Hyun-Shik Lee, Hyung Soo Yuh, Jun Koo Yi, Na Ri Kim, Si Jun Park, Seo Jin Park, Ki Beom Bae, Wan-Uk Kim, Jae-Young Kim, Hei Jung Kim, Mi Jung Shin, Byung Hwa Hyun, Zae Young Ryoo, Young Rae Ji, Du Hak Yoon, Sanggyu Lee, Dong Hoon Yu |
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| Rok vydání: | 2012 |
| Předmět: |
musculoskeletal diseases
Fibroblast-like synoviocyte Immunology Arthritis Apoptosis Mice Transgenic Inflammation Caspase 3 Biology Matrix metalloproteinase Proinflammatory cytokine Mice Rheumatology Western blot medicine Animals Immunology and Allergy Pharmacology (medical) Protein kinase B Adaptor Proteins Signal Transducing medicine.diagnostic_test Synovial Membrane medicine.disease Arthritis Experimental Matrix Metalloproteinases Cancer research Joints medicine.symptom |
| Zdroj: | Arthritis & Rheumatism. 64:2191-2200 |
| ISSN: | 0004-3591 |
| DOI: | 10.1002/art.34398 |
| Popis: | Objective 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). Methods 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. Results 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. Conclusion 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. |
| Databáze: | OpenAIRE |
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