Enhancement of CCL2 expression and monocyte migration by CCN1 in osteoblasts through inhibiting miR-518a-5p: implication of rheumatoid arthritis therapy.
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.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Cheng-Yu
CY
Chen
Department of Prosthodontics, China Medical University Hospital, Taichung, Taiwan.
Lih-Jyh
LJ
Fuh
Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
Chien-Chung
CC
Huang
School of Chinese Medicine, China Medical University, Taichung, Taiwan.|Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
Chin-Jung
CJ
Hsu
Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China.
Chen-Ming
CM
Su
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Shan-Chi
SC
Liu
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan. ymlin@vghtc.gov.tw.|Department of Orthopedic Surgery, Taichung Veterans General Hospital, Taichung, Taiwan. ymlin@vghtc.gov.tw.
Yu-Min
YM
Lin
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. chtang@mail.cmu.edu.tw.|Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan. chtang@mail.cmu.edu.tw.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan. chtang@mail.cmu.edu.tw.
Chih-Hsin
CH
Tang
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D013582:Synovial Fluid / Q000378:metabolism
C111835:CCL2 protein, human; C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; D018932:Chemokine CCL2; D055515:Cysteine-Rich Protein 61; C571457:MIRN518 microRNA, human; D035683:MicroRNAs