Dataset Information

Role of macrophage CCAAT/enhancer binding protein delta in the pathogenesis of rheumatoid arthritis in collagen-induced arthritic mice.

ABSTRACT:

Background

The up-regulation of CCAAT/enhancer binding protein delta (CEBPD) has frequently been observed in macrophages in age-associated disorders, including rheumatoid arthritis (RA). However, the role of macrophage CEBPD in the pathogenesis of RA is unclear.

Methodology and principal findings

We found that the collagen-induced arthritis (CIA) score and the number of affected paws in Cebpd(-/-) mice were significantly decreased compared with the wild-type (WT) mice. The histological analysis revealed an attenuated CIA in Cebpd(-/-) mice, as shown by reduced pannus formation and greater integrity of joint architecture in affected paws of Cebpd(-/-) mice compared with WT mice. In addition, immunohistochemistry analysis revealed decreased pannus proliferation and angiogenesis in Cebpd(-/-) mice compared with WT mice. CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. CCL20, IL23A, CXCL1 and TNFAIP6 contributed to the migration and proliferation of synoviocytes, and the latter two proteins were involved in tube formation of endothelial cells. Finally, two anti-inflammatory chemicals, inotilone and rosmanol, reduced the expression of CEBPD and its downstream targets and mitigated the above phenomena.

Conclusions and significance

Collectively, our findings suggest that CEBPD and its downstream effectors could be biomarkers for the diagnosis of RA and potentially serve as therapeutic targets for RA therapy.

SUBMITTER: Chang LH

PROVIDER: S-EPMC3454428 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Role of macrophage CCAAT/enhancer binding protein delta in the pathogenesis of rheumatoid arthritis in collagen-induced arthritic mice.

Chang Ling-Hua LH Huang Huei-Sheng HS Wu Po-Ting PT Jou I-Ming IM Pan Min-Hsiung MH Chang Wen-Chang WC Wang Dennis Ding Hwa DD Wang Ju-Ming JM

PloS one 20120924 9

<h4>Background</h4>The up-regulation of CCAAT/enhancer binding protein delta (CEBPD) has frequently been observed in macrophages in age-associated disorders, including rheumatoid arthritis (RA). However, the role of macrophage CEBPD in the pathogenesis of RA is unclear.<h4>Methodology and principal findings</h4>We found that the collagen-induced arthritis (CIA) score and the number of affected paws in Cebpd(-/-) mice were significantly decreased compared with the wild-type (WT) mice. The histolo ...[more]

PMID: 23028973

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Project description:PurposeJintiange capsule (JTG), an approved drug developed as a substitute for tiger bone (TB), has been clinically applied for osteoporosis therapy since 2003. The drug is composed of bionic TB powder, in which peptides and proteins are primarily enriched from other bone extracts. However, as a precious material of traditional Chinese medicine (TCM), TB has been mainly understood and used in TCM to relieve osteoporosis, rheumatoid arthritis and bone injury. Inspired by those, the purpose of this study was to investigate whether JTG also had an effect on relieving rheumatoid arthritis in collagen-induced arthritic (CIA) rats and explore potential mechanism from the perspective of serum metabolic profile changes.MethodsJTG was analyzed using Nano LC-MS/MS and orally administered in CIA rats for 6 weeks. After administration, intervention effects of JTG on synovial inflammation, bone micro-architecture and bone metabolism were studied, and the impact of JTG on serum metabolic profiles in CIA rats was investigated by metabolomics.ResultsNine bioactive peptides were identified in JTG. In animal treatments, JTG alleviated paw swelling (P < 0.01), arthritic severity (P < 0.01) and synovial tissue proliferation, as well as inflammatory cell infiltration of ankle joint, decreased bone loss, improved microstructure of bone in CIA rats by regulating bone absorption and formation, specifically increasing bone mineral density (BMD) (P < 0.05), bone volume fraction (BVF) (P < 0.05), trabecular number (Tb.N) (P < 0.05) and decreasing trabecular separation (Tb.Sp) (P < 0.05). Besides, serum IL-6 was down-regulated remarkably in CIA rats (P < 0.05). Furthermore, metabolomics analysis revealed that 32 metabolites were regulated significantly (P < 0.05) by comparison between CIA model and JTG in 360 mg/kg dose. The pathway analysis implied that JTG was involved in regulation of biosynthesis of phenylalanine.ConclusionJTG alleviates rheumatoid arthritis and reverses changes in serum metabolic profile in CIA rats.

Dataset Information

Role of macrophage CCAAT/enhancer binding protein delta in the pathogenesis of rheumatoid arthritis in collagen-induced arthritic mice.

Background

Methodology and principal findings

Conclusions and significance

Publications

Role of macrophage CCAAT/enhancer binding protein delta in the pathogenesis of rheumatoid arthritis in collagen-induced arthritic mice.

Similar Datasets

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