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The systemic effects of sclerostin overexpression using ΦC31 integrase in mice

 Dongdong Zhang  ;  Bo Mi Park  ;  Myengmo Kang  ;  HeeJin Nam  ;  Eun Jin Kim  ;  ChuHyun Bae  ;  Sung Kil Lim 
 Biochemical and Biophysical Research Communications, Vol.472(3) : 471-476, 2016 
Journal Title
 Biochemical and Biophysical Research Communications 
Issue Date
Animals ; Bacteriophages/enzymology* ; Bacteriophages/genetics ; Bone and Bones/metabolism* ; Bone and Bones/pathology ; Glycoproteins/blood* ; Glycoproteins/genetics* ; Integrases/genetics* ; Male ; Mice ; Mice, Inbred ICR ; Osteoporosis/classification* ; Osteoporosis/pathology ; Transfection/methods ; Up-Regulation/genetics
Bone ; Serum sclerostin ; Sost ; ΦC31 integrase
Sclerostin, encoded by the Sost gene, is mainly produced by osteocytes in bone and antagonizes the Wnt/β-catenin signaling pathway, which is a requisite for bone formation. Currently, human anti-sclerostin antibodies are being tested in phase III clinical trials. In addition, serum sclerostin levels are reported to be associated with bone mineral density and fracture risk in normal individuals; however, the correlation between serum sclerostin and bone mass remains controversial. To study the effects of the continuous exposure of exogenous sclerostin on bone, a ΦC31 integrase system, which has the characteristics of site-specificity and efficiency, was applied for the delivery of the Sost gene in this study. We injected Sost-attB plasmid with or without ΦC31 integrase plasmid into the mouse tail vein using a hydrodynamic-based method. The site-specific integration of the Sost gene into the mouse genome was confirmed by examining a pseudo-attP site on the hepatic genomic DNA. Sclerostin was expressed in the hepatocytes, secreted into the blood flow, and maintained at high concentrations in the mice with both Sost-attB plasmid and ΦC31 integrase plasmid injections, which was observed by serial measurement. Moreover, the mice with long-term high levels of serum sclerostin showed trabecular bone loss on micro-CT analysis. Peripheral B cell populations were not affected. Our results suggested that sclerostin could be expressed in the liver and sustained successfully at high levels in the blood by using the ΦC31 integrase system, leading to trabecular bone loss. These findings may help to further ascertain the effects of sclerostin introduced exogenously on the skeleton.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
강명모(Kang, Myengmo)
임승길(Lim, Sung Kil)
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