STAT3 is critical to promote inflammatory cytokines and RANKL expression in inflammatory arthritis

Takeshi Miyamoto,Toshiaki Toyama,Tomoaki Mori,Akihiko Yoshimura

doi:10.1186/ar3644

Abstract

Rheumatoid arthritis (RA) causes sever joint damage and significant disability of daily living. The symptoms of RA patients are mainly from chronic inflammation and continuous joint destruction, however, the mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unclear. In this study, we show that signal transducer and activator of transcription 3 (STAT3) plays a critical role in both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines, such as IL-1β, TNFα and IL-6, activated STAT3 either directly or indirectly and induced expression of inflammatory cytokines, further activating STAT3. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), an essential cytokine for osteoclast differentiation. STAT3 knockout or pharmacological inhibition resulted in significant reduction of the expression of both inflammatory cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen induced arthritis (CIA), in vivo through significant reduction in expression of inflammatory cytokines and RANKL, inhibiting both inflammation and joint destruction. Thus our data provide new insight into pathogenesis of RA and provide evidence that inflammatory cytokines induce a cytokine amplification loop via STAT3 that promotes sustained inflammation and joint destruction.

Highlights

Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations in a number of demyelinating disorders including multiple sclerosis (MS) and collagen diseases
tumor necrosis factor (TNF) therapy and demyelinating event: A report indicates that adverse events such as the demyelinating lesion in the brain, optic neuritis, and neuropathy occurred after treatment with anti-TNF alpha therapy in collagen disease, and TNF antagonizing therapy showed worsening in a clinical trial with MS
Believing on the similarities of normal joints in humans and monkeys, we have employed a model of collagen-induced arthritis in Macaca fascicularis in an attempt to evaluate the histological alterations caused by such condition in the extracellular matrix of the articular cartilage

Summary

Introduction

Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations in a number of demyelinating disorders including multiple sclerosis (MS) and collagen diseases. Acute Serum Amyloid A (A-SAA) is an acute phase protein strongly expressed in rheumatoid arthritis (RA) synovial tissue (ST) critically involved in regulating cell migration and angiogenesis These processes are dependent on downstream interactions between extracellular matrix and cytoskeletal components. Conclusions: These results indicate that Egr-1 contributes to IL-1mediated down-regulation of PPARg expression in OA chondrocytes and suggest that this pathway could be a potential target for pharmacologic intervention in the treatment of OA and possibly other arthritic diseases. Immune cell-derived microparticles (MPs) are present at increased amounts in synovial fluid of rheumatoid arthritis (RA) patients [1] and can activate disease-relevant signalling pathways in RA synovial fibroblasts (SF) [2,3].

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