Enhancement of CCL2 expression and monocyte migration by CCN1 in osteoblasts through inhibiting miR-518a-5p: implication of rheumatoid arthritis therapy

Cheng-Yu Chen,Chien-Chung Huang,Lih-Jyh Fuh,Chen-Ming Su,Chin-Jung Hsu,Yu-Min Lin,Shan-Chi Liu,Chih-Hsin Tang

doi:10.1038/s41598-017-00513-0

Abstract

Cysteine-rich 61 (Cyr61 or CCN1), a secreted protein from the CCN family, is an important proinflammatory cytokine. Migration and infiltration of mononuclear cells to inflammatory sites play a critical role in the pathogenesis of rheumatoid arthritis (RA). Monocyte chemoattractant protein-1 (MCP-1/CCL2) is the key chemokine that regulates migration and infiltration of monocytes. Here, we examined the role of CCN1 in monocyte migration, and CCL2 expression in osteoblasts. We found higher levels of CCN1 and CCL2 in synovial fluid from RA patients compared with levels from non-RA controls. We also found that the CCN1-induced increase in CCL2 expression is mediated by the MAPK signaling pathway and that miR-518a-5p expression was negatively regulated by CCN1 via the MAPK cascade. In contrast, inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA ameliorated articular swelling, cartilage erosion, and infiltration of monocytes in the ankle joints of mice with collagen-induced arthritis. Our study describes how CCN1 promotes monocyte migration by upregulating CCL2 expression in osteoblasts in RA disease. CCN1 could serve as a potential target for RA treatment.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder, in which the immune system attacks the healthy lining of joints[1, 2]
We found that levels of CCN1 and CCL2 were significantly higher in synovial fluid from patients with rheumatoid arthritis (RA) compared with those from non-RA patients (Fig. 1A and B)
The quantitative data showed a highly positive correlation between the expression of CCN1 and CCL2 in RA patients (Fig. 1C). These results indicate that CCN1 and CCL2 levels are elevated in RA synovial fluid

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder, in which the immune system attacks the healthy lining of joints[1, 2]. CCN1 was necessary for interleukin-17 (IL)-17-induced fibroblast-like synoviocytes proliferation[18] and promotes proinflammatory cytokine IL-1β production during the progression of RA disease[19], and enhances VEGF-A-dependent angiogenesis in RA process[20] These reports suggest that CCN1 plays a critical role in the pathogenesis of RA. In vivo results from our study show that lentiviral knockdown of CCN1 significantly abolishes bone erosion and monocyte infiltration in joints of mice with collagen-induced arthritis (CIA). These results provide new insights into the mechanisms of CCN1 action that may have therapeutic implications for patients with RA

Methods

Results

Conclusion