Retrovirus-Mediated Gene Transfer of RANK-Fc Prevents Bone Loss in Ovariectomized Mice

¹ Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
² Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

^* To whom correspondence should be addressed. E-mail: csshin{at}snu.ac.kr.

	Abstract

Postmenopausal osteoporosis is characterized by increased bone resorption due to estrogen deficiency. RANK-Fc, a fusion protein that specifically blocks RANKL binding to RANK, has been known to be efficient and well-tolerated in animal models of osteoporosis. Here we show that cell-based gene therapy with RANK-Fc effectively prevented bone loss in ovariectomized (OVX) mice. Thirty-one young adult female C57Bl/6 mice were used and repeated intraperitoneal injection of mesenchymal stem cells (MSCs) transduced with retrovirus was performed as follows: (1)Sham-operated mice (SHAM, n=8) (2) OVX mice treated with PBS (OVX-PBS, n=8) (3) OVX mice injected with MSCs transduced with control retrovirus (OVX-GFP, n=7) (4) OVX mice injected with MSCs transduced with RANK-Fc (OVX-RANK-Fc, n=8). Cellular expression of RANK-Fc was confirmed by Western blot analysis of cell lysates and conditioned medium, and also by ELISA for the mice serum. Measurement of BMD by dual energy x-ray absorptiometry (PIXImus) revealed that OVX-RANK-Fc group gained significantly higher BMD than either the OVX-PBS group or OVX-GFP group after 8 weeks. The expression of GFP, which is co-expressed with RANK-Fc was detected by PCR analysis of DNA isolated from femur and intra-abdominal fat, whereas no GFP signal was identified in liver, brain, heart, lung, or bone marrow aspirates. These suggest that expression of RANK-Fc by genetically modified MSCs may be a feasible option for the prevention of bone loss induced by OVX.

Key Words. Receptor activator of NF-B (RANK), RANK-Fc, Mesenchymal stem cell (MSC), Gene therapy, Osteoporosis, Ovariectomy (OVX)

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