title: The systemic effects of sclerostin overexpression using ΦC31 integrase in mice.
abstract: 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.
authors: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea; Division of Endocrinology & Metabolism, Department of Internal Medicine, Affiliated Yantai Hospital of Binzhou Medical University, Yantai, PR China.
authors: Dongdong
authors: D
authors: Zhang
authors: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
authors: Bo Mi
authors: BM
authors: Park
authors: Division of Endocrinology and Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Myengmo
authors: M
authors: Kang
authors: Division of Endocrinology and Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: HeeJin
authors: H
authors: Nam
authors: Division of Endocrinology and Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Eun Jin
authors: EJ
authors: Kim
authors: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
authors: ChuHyun
authors: C
authors: Bae
authors: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Republic of Korea; Division of Endocrinology and Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: lsk@yuhs.ac.
authors: Sung Kil
authors: SK
authors: Lim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001435:Bacteriophages / Q000201:enzymology* / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000097:blood* / Q000235:genetics*; D019426:Integrases / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010024:Osteoporosis / Q000145:classification* / Q000473:pathology; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D019426:Integrases
keywords: Bone; Serum sclerostin; Sost; ΦC31 integrase