Abstract:
INTRODUCTION:The c-Jun N-terminal kinase (JNK) is a key regulator of matrix metalloproteinase (MMP) and cytokine production in rheumatoid arthritis (RA) and JNK deficiency markedly protects mice in animal models of arthritis. Cytokine-induced JNK activation is strictly dependent on the mitogen-activated protein kinase kinase 7 (MKK7) in fibroblast-like synoviocytes (FLS). Therefore, we evaluated whether targeting MKK7 using anti-sense oligonucleotides (ASO) would decrease JNK activation and severity in K/BxN serum transfer arthritis. METHODS:Three 2'-O-methoxyethyl chimeric ASOs for MKK7 and control ASO were injected intravenously in normal C57BL/6 mice. PBS, control ASO or MKK7 ASO was injected from Day -8 to Day 10 in the passive K/BxN model. Ankle histology was evaluated using a semi-quantitative scoring system. Expression of MKK7 and JNK pathways was evaluated by quantitative PCR and Western blot analysis. RESULTS:MKK7 ASO decreased MKK7 mRNA and protein levels in ankles by about 40% in normal mice within three days. There was no effect of control ASO on MKK7 expression and MKK7 ASO did not affect MKK3, MKK4 or MKK6. Mice injected with MKK7 ASO had significantly less severe arthritis compared with control ASO (P < 0.01). Histologic evidence of synovial inflammation, bone erosion and cartilage damage was reduced in MKK7 ASO-treated mice (P < 0.01). MKK7 deficiency decreased phospho-JNK and phospho-c-Jun in ankle extracts (P < 0.05), but not phospho-MKK4. Interleukin-1beta (IL-1β), MMP3 and MMP13 gene expression in ankle joints were decreased by MKK7 ASO (P < 0.01). CONCLUSIONS:MKK7 plays a critical regulatory role in the JNK pathway in a murine model of arthritis. Targeting MKK7 rather than JNK could provide site and event specificity when treating synovitis.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
Lee SI,Boyle DL,Berdeja A,Firestein GSdoi
10.1186/ar3750subject
Has Abstractpub_date
2012-02-21 00:00:00pages
R38issue
1eissn
1478-6354issn
1478-6362pii
ar3750journal_volume
14pub_type
杂志文章abstract:BACKGROUND:African Americans with systemic lupus erythematosus (SLE) have increased renal disease compared to Caucasians, but differences in other comorbidities have not been well-described. We used an electronic health record (EHR) technique to test for differences in comorbidities in African Americans compared to Cau...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-018-1561-8
更新日期:2018-04-10 00:00:00
abstract::Scleroderma (systemic sclerosis; SSc) is characterised by fibrosis of the skin and internal organs in the context of autoimmunity and vascular perturbation. Overproduction of extracellular matrix components and loss of specialised epithelial structures are analogous to the process of scar formation after tissue injury...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
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journal_title:Arthritis research & therapy
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doi:10.1186/ar3185
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abstract::The characteristics of rheumatoid arthritis (RA) pathology include the infiltration of inflammatory leukocytes, the proliferation of synovial cells, and the presence of extensive angiogenesis, referred to as rheumatoid pannus. Fas ligand is critical to the homeostatic regulation of the immune response, but its role in...
journal_title:Arthritis research & therapy
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doi:10.1186/ar2181
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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abstract:INTRODUCTION:Early degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue fr...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-016-1145-4
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
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更新日期:2011-02-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar2154
更新日期:2007-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-015-0873-1
更新日期:2015-12-24 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-02218-8
更新日期:2020-06-01 00:00:00
abstract::Recent genome-wide association studies have advanced our understanding of genetic factors that underlie systemic lupus erythematosus (SLE), a multifactorial autoimmune disease characterized by various clinical manifestations. SLE also has an environmental component, which can trigger or exacerbate the disease. Despite...
journal_title:Arthritis research & therapy
pub_type: 评论,社论
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更新日期:2011-05-31 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-016-1061-7
更新日期:2016-07-07 00:00:00
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journal_title:Arthritis research & therapy
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doi:10.1186/s13075-017-1447-1
更新日期:2017-11-02 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar4027
更新日期:2012-08-31 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-018-1575-2
更新日期:2018-05-02 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-019-1820-3
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar2141
更新日期:2007-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
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更新日期:2012-07-20 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 评论,社论
doi:10.1186/ar2993
更新日期:2010-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar2340
更新日期:2007-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar1733
更新日期:2005-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar2686
更新日期:2009-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-015-0575-8
更新日期:2015-03-23 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar1798
更新日期:2005-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4265
更新日期:2013-08-14 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar2500
更新日期:2008-01-01 00:00:00