Evaluation of osteoclastogenesis via NFκB decoy/mannosylated cationic liposome-mediated inhibition of pro-inflammatory cytokine production from primary cultured macrophages.
OBJECTIVE
To explore the effect of NFκB activation in macrophages on osteoclastogenesis of bone marrow cells for potential application as a new type of therapy for preventing bone loss.


METHODS
Primary cultured macrophages and bone marrow cells were prepared from mice. As macrophage-targeted carriers, Mannosylated cationic liposomes (Man-liposomes) were prepared and were allowed to form complexes with NFκB decoy (a double-stranded oligonucleotide). Cellular uptake, inhibition of NFκB activation, and cytokine production were evaluated using macrophages. Osteoclastogenesis was investigated using bone marrow cells, which were cultured in the conditioned medium prepared from macrophages with or without Man-liposome/NFκB decoy complexes treatment.


RESULTS
Cellular accumulation of NFκB decoy was enhanced by Man-liposome. NFκB activation in macrophages and TNF-α production were suppressed in macrophages by Man-liposome/NFκB decoy complexes but not by the naked NFκB decoy, Gal-liposome/NFκB decoy complexes, or Man-liposome/random decoy complexes. Osteoclastogenesis of bone marrow cells was induced in the conditioned medium prepared from activated macrophages but not by activated macrophages treated with Man-liposome/NFκB decoy complexes.


CONCLUSIONS
Osteoclastogenesis induced by activated macrophages could be suppressed by the treatment macrophages with Man-liposome/NFκB decoy complexes. Macrophage-targeted delivery of NFκB decoys using Man-liposomes may be promising in its use for the remediation of bone loss.
Department of Drug Delivery Research Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29, Yoshida-shimoadachi, Sakyo-ku, Kyoto, 606-8501, Japan.
Thuy Duong
TD
Dinh
Yuriko
Y
Higuchi
Shigeru
S
Kawakami
Fumiyoshi
F
Yamashita
Mitsuru
M
Hashida
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D001862:Bone Resorption / Q000276:immunology / Q000517:prevention & control; D002412:Cations; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D008358:Mannose / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology; D010316:Particle Size
D002412:Cations; D016207:Cytokines; D004337:Drug Carriers; D008070:Lipopolysaccharides; D008081:Liposomes; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D008358:Mannose
J Gene Med. 2005 Jun;7(6):771-81
15702489
Oligonucleotides. 2008 Dec;18(4):305-19
19025401
Annu Rev Pathol. 2008;3:457-84
18039135
J Hepatol. 2006 Apr;44(4):742-8
16469408
Trends Pharmacol Sci. 1997 Jan;18(1):12-8
9114724
Gene Ther. 2000 Feb;7(4):292-9
10694809
Biol Pharm Bull. 2006 Jul;29(7):1516-20
16819203
Arch Biochem Biophys. 2008 May 15;473(2):139-46
18395508
Immunol Rev. 2005 Dec;208:80-7
16313342
J Pharm Sci. 2008 Feb;97(2):726-45
17823947
BioDrugs. 2010 Jun;24(3):195-205
20462284
Mol Pharmacol. 1994 May;45(5):932-43
8190109
J Bone Miner Res. 2007 May;22(5):724-9
17295604
Biochem Pharmacol. 1996 Jan 26;51(2):173-82
8615886
Mol Pharmacol. 2005 Apr;67(4):1018-25
15576632
J Control Release. 2011 Jan 5;149(1):42-50
20035809
J Biol Chem. 2000 Sep 1;275(35):27307-10
10874036
J Clin Invest. 2003 Apr;111(8):1221-30
12697741
Arthritis Res Ther. 2006;8(1):201
16356195
EMBO J. 1991 Dec;10(13):4025-31
1721867
Clin Exp Immunol. 2010 Jul 1;161(1):1-9
20491796
J Control Release. 2008 Jan 22;125(2):131-6
18045722
Pharmazie. 2006 Feb;61(2):144-7
16526563
Gene Ther. 2006 Jun;13(12):933-41
16511526
FEBS Lett. 2006 Jun 26;580(15):3706-14
16765948
J Clin Invest. 1996 Sep 1;98(5):1119-29
8787674
Ann Rheum Dis. 2010 Aug;69(8):1415-9
20650876
Oncogene. 1999 Nov 22;18(49):6853-66
10602461
Nat Rev Rheumatol. 2009 Oct;5(10):578-82
19798034
Bioorg Med Chem. 2009 Jul 15;17(14):4990-5
19539484
Nat Med. 1997 Aug;3(8):894-9
9256281
Curr Drug Targets. 2004 Nov;5(8):717-33
15578952
J Control Release. 2000 May 15;66(2-3):255-69
10742585
Am J Physiol Lung Cell Mol Physiol. 2004 Dec;287(6):L1248-55
15298852
Am J Respir Cell Mol Biol. 1997 Jul;17(1):3-9
9224203