Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation–inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)6) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)6-liposome as a promising targeted delivery system for RNA interference–based bone anabolic therapy.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Black, D.M. et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N. Engl. J. Med. 349, 1207–1215 (2003).
Hodsman, A.B. et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr. Rev. 26, 688–703 (2005).
Cosman, F. et al. Daily and cyclic parathyroid hormone in women receiving alendronate. N. Engl. J. Med. 353, 566–575 (2005).
Lindsay, R. et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 350, 550–555 (1997).
Neer, R.M. et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344, 1434–1441 (2001).
López-Fraga, M., Martinez, T. & Jimenez, A. RNA interference technologies and therapeutics: from basic research to products. BioDrugs 23, 305–332 (2009).
Novina, C.D. & Sharp, P.A. The RNAi revolution. Nature 430, 161–164 (2004).
Itaka, K. et al. Bone regeneration by regulated in vivo gene transfer using biocompatible polyplex nanomicelles. Mol. Ther. 15, 1655–1662 (2007).
Wang, D., Miller, S.C., Kopeckova, P. & Kopecek, J. Bone-targeting macromolecular therapeutics. Adv. Drug Deliv. Rev. 57, 1049–1076 (2005).
Wang, D. et al. Osteotropic peptide that differentiates functional domains of the skeleton. Bioconjug. Chem. 18, 1375–1378 (2007).
Yarbrough, D.K. et al. Specific binding and mineralization of calcified surfaces by small peptides. Calcif. Tissue Int. 86, 58–66 (2010).
Lu, K. et al. Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by Ckip-1. Nat. Cell Biol. 10, 994–1002 (2008).
Zhang, L. et al. The PH domain containing protein Ckip-1 binds to IFP35 and Nmi and is involved in cytokine signaling. Cell. Signal. 19, 932–944 (2007).
Stuart, A.J. & Smith, D.A. Use of the fluorochromes xylenol orange, calcein green, and tetracycline to document bone deposition and remodeling in healing fractures in chickens. Avian Dis. 36, 447–449 (1992).
Aubin, J. & JNM., H. Bone cell biology: osteoblast, osteocyte and osteoclasts. in Pediatric Bone 43–47 (Academic Press, San Diego, California, USA, 2002).
Gronthos, S. et al. Differential cell surface expression of the STRO-1 and alkaline phosphatase antigens on discrete developmental stages in primary cultures of human bone cells. J. Bone Miner. Res. 14, 47–56 (1999).
Ishikawa, S. et al. Involvement of FcRγ in signal transduction of osteoclast-associated receptor (OSCAR). Int. Immunol. 16, 1019–1025 (2004).
Kim, N., Takami, M., Rho, J., Josien, R. & Choi, Y. A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J. Exp. Med. 195, 201–209 (2002).
Posner, A.S. & Betts, F. Synthetic amorphous calcium-phosphate and its relation to bone-mineral structure. Acc. Chem. Res. 8, 273–281 (1975).
Hoang, Q.Q., Sicheri, F., Howard, A.J. & Yang, D.S. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature 425, 977–980 (2003).
Midura, R.J. et al. Bone acidic glycoprotein-75 delineates the extracellular sites of future bone sialoprotein accumulation and apatite nucleation in osteoblastic cultures. J. Biol. Chem. 279, 25464–25473 (2004).
Steitz, S.A. et al. Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification. Am. J. Pathol. 161, 2035–2046 (2002).
Takahashi-Nishioka, T. et al. Targeted drug delivery to bone: pharmacokinetic and pharmacological properties of acidic oligopeptide-tagged drugs. Curr. Drug Discov. Technol. 5, 39–48 (2008).
Wang, D., Miller, S., Sima, M., Kopeckova, P. & Kopecek, J. Synthesis and evaluation of water-soluble polymeric bone-targeted drug delivery systems. Bioconjug. Chem. 14, 853–859 (2003).
Federman, N. & Denny, C.T. Targeting liposomes toward novel pediatric anticancer therapeutics. Pediatr. Res. 67, 514–519 (2010).
Wang, G., Kucharski, C., Lin, X. & Uludag, H. Bisphosphonate-coated BSA nanoparticles lack bone targeting after systemic administration. J. Drug Target. 18, 611–626 (2010).
Cullis, P.R., Mayer, L.D., Bally, M.B., Madden, T.D. & Hope, M.J. Generating and loading of liposomal systems for drug-delivery applications. Adv. Drug Deliv. Rev. 3, 267–282 (1989).
Vegni, F.E., Corradini, C. & Privitera, G. Effects of parathyroid hormone and alendronate alone or in combination in osteoporosis. N. Engl. J. Med. 350, 189–192, author reply 189–192 (2004).
We thank X.-H. Yang for technical support with the confocal imaging, H. Yang for technical support with the flow cytometry and F.C. Chun-Wan for assistance with the bone histomorphometry. This study was supported by the Chinese National Basic Research Programs (2011CB910602), the Hong Kong Competitive Earmarked Research Grant (CUHK479111 and 473011), the Direct Grant of Faculty of Medicine of the Chinese University of Hong Kong (2041478 and 2041525), the Faculty Research Grant of Hong Kong Baptist University (30-08-089), the Chinese National Natural Science Foundation Project (30830029) and the National Key Technologies Research and Development Program for New Drugs (2009ZX09503-002).
The authors declare no competing financial interests.
About this article
International Journal of Molecular Sciences (2019)
International Journal of Oral Science (2019)
Current Progress on MicroRNA-Based Gene Delivery in the Treatment of Osteoporosis and Osteoporotic Fracture
International Journal of Endocrinology (2019)
Tissue Engineering Part A (2019)
A Carboxyl-Terminated Dendrimer Enables Osteolytic Lesion Targeting and Photothermal Ablation of Malignant Bone Tumors
ACS Applied Materials & Interfaces (2019)