title: Inhibition of osteoclastogenesis through siRNA delivery with tunable mesoporous bioactive nanocarriers.
abstract: Gene silencing through siRNA delivery has shown great promise for treating diseases and repairing damaged tissues, including bone. This report is the first to develop siRNA delivery system in the inhibition of osteoclastic functions which in turn can help turn-over bone mass increase in the diseases like osteoporosis. For this reason, biocompatible and degradable nanocarriers that can effectively load and deliver genetic molecules to target cells and tissues are being actively sought by researchers. In this study, mesoporous bioactive glass nanospheres (MBG), a novel unique biocompatible degradable inorganic nanocarrier, is introduced. Furthermore, siRNA was designed to function by inhibiting the expression of the receptor activator of nuclear factor kappa B (RANK) in order to suppress osteoclastogenesis. Amine-functionalized MBG were synthesized with tunable mesoporosities, showing a strong complexation with siRNA. An in vitro release profile indicated that the siRNA from the MBG was able to achieve a highly sustainable liberation for up to 4 days, confirming a temporary delivery system can be designed to function for that period of time. The intracellular uptake capacity of the complex siRNA(RANK)-MBG was recorded to be around 70%. Furthermore, the RANK-expressing cell population declined down to 29% due to the delivery of siRNA(RANK)-MBG (vs. 86% in control). The expression of osteoclastogenesis-related genes, including c-fos, cathepsin-K, tartrate-resistant acid phosphatase (TRAP), and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), was substantially down-regulated by the siRNA delivery system. This study reports for the first time on the use of a novel MBG delivery system for siRNA that aims to suppress osteoclastic actions. MBGs may be a potential gene delivery platform for hard tissue repair and disease treatment due to the collective results which indicate a high loading capacity, temporary release kinetics, high intracellular uptake rate, and sufficient gene silencing effects, together with the intrinsic beneficial properties like bone-bioactivity and degradability.
  
  
  CONCLUSIONS
  This report is the first to develop siRNA delivery system of biocompatible and degradable nanocarriers made from a unique composition, i.e., mesoporous bioactive glass that can effectively load and deliver genetic molecules to osteoclastic cells. We proved through a series of studies that the biocompatible nanocarriers are effective for the delivery of siRNA in the inhibition of osteoclastic functions which thus might be considered as a nanocarrier platform to help turn-over bone mass increase in the diseases like osteoporosis.
authors.affiliation: Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, South Korea; Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, South Korea.
authors.forename: Tae-Hyun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, South Korea; Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, South Korea.
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, South Korea; Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, South Korea.
authors.forename: Min Sil
authors.initials: MS
authors.lastname: Kang
authors.affiliation: Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, South Korea; Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, South Korea.
authors.forename: Joong-Huyn
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, South Korea; Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, South Korea; Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan 330-714, South Korea. Electronic address: kimhw@dku.edu.
authors.forename: Hae-Won
authors.initials: HW
authors.lastname: Kim
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D020868:Gene Silencing; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010010:Osteoclasts / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000943:Antigens, Differentiation; D004337:Drug Carriers; D034741:RNA, Small Interfering
keywords: Mesoporous bioactive glass; Nanocarriers; Osteoclast inhibition; RANK; siRNA delivery