A bone-targeting drug-delivery system based on Semaphorin 3A gene therapy ameliorates bone loss in osteoporotic ovariectomized mice

  • Bone. 2018 Sep:114:40-49. doi: 10.1016/j.bone.2018.06.003.
K Yang  1 ,  R J Miron  2 ,  Z Bian  3 ,  Y F Zhang  4
Affiliations
  • 1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • 2. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Periodontology, Cell Therapy Institute, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, Florida, USA.
  • 3. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Endodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China. Electronic address: [email protected].
  • 4. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Dental Implantology, School and Hospital of Stomatology, Wuhan University, Wuhan, China. Electronic address: [email protected].
PMID: 29883786 DOI: 10.1016/j.bone.2018.06.003
Abstract

Osteoporosis is a serious health problem worldwide. Semaphorins (Sema) have been described as key molecules involved in the cross-talk between bone cells (osteoblasts/osteoclasts). In this study, we investigated whether plasmid containing Sema3a could ameliorate bone loss in an ovariectomized (OVX) mouse model via (AspSerSer)6, a selectively bone-targeting moiety. Plasmid pcDNA3.1(+)-Sema3a-GFP was fabricated and transfected cells with the plasmid demonstrated statistically higher levels of Sema3A in vitro (p < 0.001). Mice were ovariectomized and injected twice weekly with (AspSerSer)6-(STR-R8)+pcDNA3.1(+)-Sema3a-GFP for four weeks. The aim of the study was twofold: firstly to design an effective bone-targeting drug-delivery system (AspSerSer)6. Secondly, the effects of Sem3A gene therapy on bone loss was investigated. Here, the targeting selectivity of pcDNA3.1(+)-Sema3a-GFP via (AspSerSer)6 to the trabecular bone surface was firstly verified by histological observation of frozen sections and immunofluorescence staining. Then, bone microstructure analysis by Micro-CT indicated significantly less bone loss in mice treated with (AspSerSer)6-(STR-R8)+pcDNA3.1(+)-Sema3a-GFP compared to the control group (p < 0.05). Furthermore,H&E staining and Safranin O staining of the decalcified sections demonstrated statistically significantly higher bone area/total area in the mice that were injected with (AspSerSer)6-(STR-R8)+pcDNA3.1(+)-Sema3a-GFP (p < 0.001, p < 0.01,respectively). TRAP staining and immunohistochemistry staining of COL I demonstrated lower numbers of osteoclasts and significantly increased numbers of osteoblasts in the bone-targeting moiety delivering pcDNA3.1(+)-Sema3a-GFP group, when compared to the control group (p < 0.01, p < 0.001,respectively). Together, our findings have identified that, (AspSerSer)6, a bone-targeting drug-delivery system based on semaphorin3A gene therapy, ameliorated bone loss in osteoporotic ovariectomized mice, by suppressing osteoclastic bone resorption and simultaneously increasing osteoblastic bone formation. Gene therapy by local site-specific Sema3A overexpression might be a potential new strategy for treating osteoporosis and bone defects.

Keywords
(AspSerSer)(6); Bone targeting; Osteoporosis; Semaphorin3A.
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