Bone-protective effects of nonviral gene therapy with folate-chitosan DNA nanoparticle containing interleukin-1 receptor antagonist gene in rats with adjuvant-induced arthritis.
Interleukin-1 receptor antagonist (IL-1Ra), is a natural blocker of the inflammatory cytokine interleukin-1. Using a rat adjuvant-induced arthritis (AIA) model of rheumatoid arthritis (RA), we examined the protective effects of IL-1Ra in bone metabolism in vivo after folate-mediated nonviral gene delivery. We detected secreted human IL-1Ra protein in serum and cultured primary osteoblasts of rats that were treated with chitosan-IL-1Ra and folate-IL-1Ra-chitosan nanoparticles, respectively. In vivo, IL-1Ra gene delivery significantly reverted alterations in bone turnover observed in arthritic animals by modulating the level of osteocalcin (OC) as well as the activities of alkaline phosphatase and tartrate-resistant acid phosphatase. The protective effects of these nanoparticles were evident from the decrease in the expression levels of interleukine-1beta and prostaglandin E(2) as well as osteoclast number and other histopathological findings. Compared to naked DNA and chitosan-DNA, folate-chitosan-DNA nanoparticles were less cytotoxic and enhanced IL-1Ra protein synthesis in vitro and offered a better protection against inflammation and abnormal bone metabolism in vivo. Nonviral gene therapy with folate-chitosan-DNA nanoparticles containing the IL-1 Ra gene seemed to protect against bone damage and inflammation in rat adjuvant-induced arthritis model.
Fernandes
Julio C
JC
Orthopaedics Research Laboratory, Research Center, Sacré-Coeur Hospital, University of Montreal, Montreal, Quebec, Canada.
Wang
Huijie
H
Jreyssaty
Christian
C
Benderdour
Mohamed
M
Lavigne
Patrick
P
Qiu
Xingpin
X
Winnik
Francoise M
FM
Zhang
Xiaoling
X
Dai
Kerong
K
Shi
Qin
Q
D000135:Acid Phosphatase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D048271:Chitosan / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D015232:Dinoprostone / Q000097:blood; D005492:Folic Acid / Q000737:chemistry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D053583:Interleukin-1beta / Q000097:blood; D007527:Isoenzymes / Q000097:blood; D053758:Nanoparticles / Q000737:chemistry; D010006:Osteoblasts / Q000378:metabolism; D051381:Rats; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D048271:Chitosan; D005492:Folic Acid; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D015232:Dinoprostone