Brief report: amelioration of collagen-induced arthritis in mice by lentivirus-mediated silencing of microRNA-223.
OBJECTIVE
MicroRNA (miRNA) plays a role in autoimmune diseases. MiRNA-223 (miR-223) is up-regulated in patients with rheumatoid arthritis (RA) and is involved in osteoclastogenesis, which contributes to erosive disease. The aim of this study was to test the feasibility of using lentiviral vectors expressing the miR-223 target sequence (miR-223T) to suppress miR-223 activity as a therapeutic strategy in a mouse model of collagen-induced arthritis (CIA).


METHODS
Levels of miR-223 in the synovial tissue of patients with RA or osteoarthritis (OA), as well as in the ankle joints of mice with CIA, were determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Lentiviral vectors expressing miR-223T (LVmiR-223T) or luciferase short hairpin RNA (LVshLuc) as a control vector were injected intraperitoneally into mice with CIA. Treatment responses and disease-related bone mineral density were monitored. Levels of nuclear factor 1A (NF-1A), a direct target of miR-223, and macrophage colony-stimulating factor receptor (M-CSFR), which is critical for osteoclastogenesis, were measured by immunohistochemistry and quantitative RT-PCR. Osteoclasts were assessed by tartrate-resistant acid phosphatase staining.


RESULTS
MiR-223 expression was significantly higher in the synovium of RA patients and in the ankle joints of mice with CIA as compared to OA patients and normal mice. LVmiR-223T treatment reduced the arthritis score, histologic score, miR-223 expression, osteoclastogenesis, and bone erosion in mice with CIA. Down-regulation of miR-223 with concomitant increases in NF-1A levels and decreases in M-CSFR levels was detected in the synovium of LVmiR-223T-treated mice.


CONCLUSIONS
This study is the first to demonstrate that lentivirus-mediated silencing of miR-223 can reduce disease severity of experimental arthritis. Furthermore, our results indicate that inhibition of miR-223 activity should be further explored as a therapeutic strategy in RA.
National Cheng Kung University Medical College, Tainan, Taiwan.
Yuan-Tsung
YT
Li
Shih-Yao
SY
Chen
Chrong-Reen
CR
Wang
Ming-Fei
MF
Liu
Chi-Chen
CC
Lin
I-Ming
IM
Jou
Ai-Li
AL
Shiau
Chao-Liang
CL
Wu
D000818:Animals; D000843:Ankle Joint / Q000378:metabolism / Q000473:pathology; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015519:Bone Density / Q000235:genetics; D004195:Disease Models, Animal; D020868:Gene Silencing; D006801:Humans; D016086:Lentivirus; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology
C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs